IntechOpen

Home > Books > Auditory System - Function and Disorders

Open access peer-reviewed chapter

Nonreceptor Protein Kinases and Phosphatases Necessary for Auditory Function

Written By

Sadaf Naz

Submitted: 14 March 2022 Reviewed: 16 May 2022 Published: 13 July 2022

DOI: 10.5772/intechopen.105425

Auditory System IntechOpen
Auditory System Function and Disorders Edited by Sadaf Naz

From the Edited Volume

Auditory System - Function and Disorders

Edited by Sadaf Naz

Book Details Order Print

Chapter metrics overview

106 Chapter Downloads

View Full Metrics
Advertisement

Abstract

Phosphorylation is one of the most common posttranslational protein modifications. It has multiple roles in cell signaling during development as well as for maintenance of diverse functions of an organism. Protein kinases and phosphatases control phosphorylation and play critical roles in cellular processes from cell birth to cell death. Discovery of hearing-loss-associated gene variants in humans and the study of animal models have identified a crucial role of a plethora of protein phosphatases and kinases in the inner ear. In this review, those nonreceptor kinases or phosphatases are discussed, which are encoded by genes implicated in causing inherited hearing loss in humans or in mouse mutants. These studies have served to highlight the essential roles of protein kinases and phosphatases pathways to the function of the auditory system. However, the inner-ear-specific substrates for most of these enzymes remain to be discovered, as do the mechanisms of disease due to the variants in the genes that encode these proteins.

Keywords

  • audition
  • deafness
  • dephosphorylation
  • hearing
  • phosphorylation

1. Introduction

Different protein posttranslational modifications have been identified, which are necessary for hearing [1]. Among these, protein phosphorylation is a prominent and an important contributor to the development of the ear and control of audition. Phosphorylation is carried out by kinases using ɣ-phosphate from adenosine triphosphate as a donor to any of the three hydroxylated amino acids within the target protein. The removal of the phosphate group from the phosphorylated tyrosine, serine, or threonine residues of the proteins is catalyzed by phosphatases. Phosphorylation and dephosphorylation serve to change the polarity of the target proteins with profound consequences for protein conformation and interaction with other proteins [2].

Enzymes controlling phosphorylation can be categorized into receptor or nonreceptor protein kinases and phosphatases. Many phosphorylated proteins as well as enzymes that control these reactions have important roles in the auditory system [1]. Though variants in all genes encoding these proteins do not result in deafness; variants of some protein kinases and phosphatases have been reported to cause genetic hearing loss in humans or mice models, and these are presented here. Receptor kinases or receptor phosphatases important for hearing are discussed elsewhere [3] and are excluded from the discussion, as are those kinases or phosphatases that catalyze the phosphorylation or dephosphorylation of non-proteinaceous biomolecules.

Variants of most of the genes encoding protein kinases or phosphatases have been reported to cause syndromic hearing loss (Table 1). In syndromic cases, deafness is just one of the accompanying features in a spectrum of other disorder/s affecting different organs. Syndromic deafness occurs due to the importance of the protein to other systems besides the ear. The hearing loss may be present in all individuals affected by a particular syndrome, while for others it affects only a few patients diagnosed with that syndrome. In contrast, hearing loss is the sole manifestation in an individual with nonsyndromic deafness [4].

NameHGNC/OMIMAliasFunctionHuman Disorder/OMIM/Inheritance/ OR mouse phenotypeReference*
Protein Kinases
Dual-Specificity Kinases (CMGC group)
Dual-specificity tYrosine phosphorylation-Regulated Kinase 1ADYRK1A/ 600,855DYRK1General role in the MAPK pathwayMental retardation, autosomal dominant 7/614104/AD[11]
Dual-Specificity Kinases (STE Group)
Mitogen-Activated Protein Kinase kinase 1MAP2K1/615279PRKMK1
MAPKK1
MKK1
MEK1		General role in MAPK phosphorylationNoonan syndrome-like/NA/AD
Cardiofaciocutaneous syndrome 3/615279/AD		[12]
[13]
Protein Serine/Threonine Kinases (AGC Group)
CDC42-Binding Protein kinase, BetaCDC42BPB/614062MRCKBGeneral role in proliferationNeurodevelopmental phenotype/NA/AD[15]
Protein Kinase C, BetaPRKCB/176970PRKCB1
PKCB		Histone H3 phosphorylationMeniere’s disease with hearing loss/NA/AD[23]
PRotein Kinase C, GammaPRKCG/176980PKCC
PKCG		General role in developmentSpinocerebellar Ataxia 14/605361/AD[20]
Protein Serine/Threonine Kinases (AGC CAMK Group)
Ribosomal Protein S6 Kinase A3RPS6KA3/300075ISPK1
MAPKAPK1B
RSK2		Histone H3 and PDZ domain-containing proteins’ phosphorylationCoffin-Lowry Syndrome/303600/XLD[21]
Protein Serine/Threonine Kinases (CAMK Group)
Calcium/Calmodulin-dependent Serine Protein KinaseCASK/300172CMG
LIN2		Interacts with prestin and whirlin in the inner earIntellectual developmental disorder with microcephaly and pontine and cerebellar hypoplasia/300749/ XLD[7]
Mitogen-Activated Protein Kinase-Activated Protein Kinase 5MAPKAPK5/ 606,723MK5
PRAK		Heat shock protein HSP27 phosphorylationDevelopmental disorder with hearing loss/NA/AR[22]
Serine/Threonine protein Kinase 11STK11/LKB1Maintenance of stereocilia by phosphorylation of radixin, eosin and moesin, Planar cell polarity, formation of cochlear hair cellsNo hearing loss phenotype in humans/Ear specific, Atoh1cre, Lkb1−/− mice have hearing deficits[32]
Protein Serine/Threonine Kinases (CMGC Group)
Cyclin-Dependent Kinase 5CDK5/123831PSSALREMaintenance of stereocilia by phosphorylation of radixin, eosin and moesinNo hearing loss phenotype in humans/ Ear specific, Atoh1Cre/+;Cdk5lox/lox mice have hearing loss[10]
Cyclin-Dependent Kinase 8CDK8/603184K35Component of RNA polymerase II holoenzyme where kinase function phosphorylates POLR2AIntellectual developmental disorder with hypotonia and behavioral abnormalities/ 618,748/AD[16]
Cyclin-Dependent Kinase 9CDK9/ 603,251CTK1
PITALRE		Phosphorylates POLR2ACHARGE syndrome-like/NA/AR[17]
Cyclin-Dependent Kinase 10CDK10/603464PISSLREGeneral role in ciliogenesis and elongation of the primary ciliumAl Kaissi Syndrome/617694/AR[18]
Cyclin-Dependent Kinase 13CDK13/ 603,309CDC2L5
CHED		Phosphorylates the large subunit RBP1Wolfram-like syndrome/NA/AR[19]
Mitogen-Activated Protein Kinase 1MAPK1/176948ERK2,
p42MAPK
PRKM1
PRKM2		Survival of hair cells in response to noise and multiple general roles in MAPK signalingNo hearing loss phenotype in humans/Ear-specific knockout mice are susceptible to noise-induced hearing loss[33]
Protein Serine/Threonine kinases (STE Group)
Mitogen-Activated Protein Kinase Kinase Kinase 1MAP3K1/600982MAPKKK1
MEK
MEKK1		Phosphorylation of MAPK14 in cochlea and general role in MAPK signalingNo hearing loss phenotype in humans/Knockout mice are deaf[28, 29]
Mitogen-Activated Protein Kinase Kinase Kinase 4MAP3K4/602425MAPKKK4
MEKK4
MTK1		FGFR1 signaling control and general role in MAPK signalingNo hearing loss phenotype in humans/Knock-in Mekk4K1361R/ K1361R/ mice are deaf[30]
Mitogen-Activated Protein Kinase Kinase Kinase 7MAP3K7/602614TAK1a
TAK1b
TAK1c
TAK1d		Phosphorylation of MAPK14, mediates BMP and TGFB signaling, general role in MAPK signalingCardiospondylocarpofacial syndrome/157800/AD
Frontometaphyseal dysplasia 2/617137/AD		[14]
Myosin IIIAMYO3A/606808NASelf-regulation of MYO3A motor domain activityDeafness, autosomal recessive 30/607101/AR
Deafness, autosomal dominant/NA/AD		[5]
[36]
p21 Protein-Activated Kinase 1PAK1/602590NAMaintenance of hair cells and stereocilia by phosphorylation of cofilin and ezrin-radixin-moesin (ERM) and βII-spectrinNo hearing loss phenotype in humans/
Knockout mice have hearing loss		[31]
Protein Serine/Threonine Kinases (TKL Group)
B-RAF protooncogene, serine/threonine kinaseBRAF/ 164,757BRAF1
RAFB1		MAPK/ERK
pathway		LEOPARD syndrome 3,613,707/AD[24]
Mitogen-Activated Protein Kinase Kinase Kinase 20MAP3K20/609479MLTK
MRK
ZAK		MAPK/ERK
Pathway, general role in MAPK signaling		Split-foot malformation with mesoaxial polydactyly/ 616,890/AR[26]
RAF1 protooncogene, serine/threonine kinaseRAF1/164760CRAFRAS/MAPK pathwayLeopard syndrome 2/ 611,554/AD[25]
Protein Tyrosine Kinases, non-receptor class (TK Group)
ABL protooncogene 1, nonreceptor Tyrosine KinaseABL1/189980ABLGeneral role in cell cycle functionCongenital heart defects and skeletal malformations syndrome/ 617,602/AD[40, 41]
Bruton Agammaglobulinemia Tyrosine KinaseBTK/300300ATK
BPK		General role in maturation of B cells. Antibody response is thought to reduce hearing loss occurring due to infectionsAgammaglobulinemia, X-linked 1/300755/XLR[42]
Protein Phosphatases
Atypical Protein Phosphatases (HAD fold, EYA Family)
EYA transcriptional coactivator and phosphatase 1EYA1/601653NADevelopment of components of the outer middle and inner earBranchiootorenal syndrome 1, with or without cataracts/ 113,650/AD
Branchiootic Syndrome 1/
602,588/AD		[46]
[47]
EYA transcriptional coactivator and phosphatase 4EYA4/603550NAPost-developmental function of Organ of cortiDeafness, autosomal dominant 10/
601,316/AD
Cardiomyopathy, dilated, 1 J/ 605,362/AD		[49]
[50]
Dual-Specificity Phosphatases (CC1 fold, DSP family)
Cell Division Cycle 14ACDC14A/603504CDC14Conservation of hair cellsDeafness, autosomal recessive 32, with or without immotile sperm/608653/AR[52, 53]
Dual-Specificity Phosphatase 1DUSP1/600714CL100
PTPN10
MKP1		MAPK dephosphorylation, Regulation of oxidative balance and inflammatory immune response in the earNo hearing loss phenotype in humans/
Knockout mice have a progressive hearing loss		[55, 56]
Dual-Specificity Phosphatase 6DUSP6/602748MKP3
PYST1		MAPK1 dephosphorylation,
Negative regulation of FGF signaling pathway in ear development		Hypogonadotropic hypogonadism 19 with or without anosmia/615269/
AD (HL in some patients)		[59]
Dual-Specificity Phosphatases (CC1 fold, PTEN family)
Phosphatase and Tensin HomologPTEN/601728MMAC1
PTEN1		Cell cycle regulation and exit of auditory sensory progenitorsCowden syndrome 1/
158,350/AD		[64]
Protein Tyrosine Phosphatases, nonreceptor-type (CC1 fold, PTP family)
Protein-Tyrosine Phosphatase, nonreceptor-type, 11PTPN11/176876PTP2C
SHP2		Regulates
RAS/MAPK signaling pathway		Leopard Syndrome 1/ 151,100/AD
Nonsyndromic hearing loss/NA/AD
Noonan Syndrome 1/
163,950/AD		[65]
[68]
[66]

Table 1.

Nonreceptor protein kinases and phosphatases implicated in hearing loss.

Reference to the report of auditory phenotype in mice is only provided if hearing loss has not been described in humans. Classification of the protein kinases and the protein phosphatases is from Manning et al. 2002 [ref. 6] and Chen et al. 2018 [ref. 43], respectively.


HGNC=HUGO Gene Nomenclature Committee, OMIM = Online Mendelian Inheritance in Man, AD = Autosomal Dominant, AR = Autosomal Recessive, XLD = X-linked Dominant, XLR = X-linked Recessive, CMGC=Cyclin-dependent kinases (CDK), Mitogen-activated protein kinases (MAPK), Glycogen synthase kinase (GSK3) and CDC-like kinase (CLK) group of protein kinases, STE = Sterile group of Kinases, CAMK=Ca2+/calModulin-dependent protein Kinase, TKL = Tyrosine Kinase Like, TK = Tyrosine Kinase, AGC = cyclic AMP-dependent kinases (PKA), cGMP-dependent kinases, and the diacylglycerol-activated/phospholipid-dependent kinase PKC group of kinases, HAD = Haloacid Dehalogenase, EYA = Eyes Absent, CC1 = Cysteine-based Class 1, DSP=Dual-specific phosphatase, PTP=Protein Tyrosine Phosphatase, NA = Not available.

1.1 Auditory system and hearing

The auditory system in humans has distinct parts, which include the outer ear, the middle ear, and the inner ear. Sound is perceived and processed by the ear with the final stimulus conveyed to the auditory cortex in the brain. The outer and the middle ears play important roles in conveying the sound to the cochlea within the inner ear. The cochlea is a coiled structure and contains the organ of Corti, which has the sensory receptors, termed as outer and inner hair cells. All hair cells have mechano-sensitive microvilli projections at their apical ends, termed as stereocilia, which have important roles for their function [3]. True cilia, called the kinocilia, are also present, but these disappear early during maturation of the mammalian auditory system. The hair cells amplify the sound and transduce it into an electrical stimulus. The electric stimulus from the inner hair cells is finally conveyed to the brain via the spiral ganglion neurons.

1.2 Hearing loss and its types

A partial or a complete inability to hear sound is a common sensory disorder and is termed as hearing loss or deafness. Worldwide, both children and adults are affected, and approximately 430 million individuals are reported to suffer from a hearing loss (World Health Organization, 2021, https://www.who.int/news-room/fact-sheets/detail/deafness-and-hearing-loss). Deafness is categorized into four types on the basis of the affected part. Conductive hearing loss arises as a result of impedance of passage of sound through the external ear and/or the middle ear. Sensorineural hearing loss is caused by malfunction of the inner ear (cochlea or auditory nerve). Mixed hearing loss is a combination of both conductive and sensorineural hearing loss. Central auditory processing disorder results due to damage or malfunction at the cranial nerves, the cerebral cortex, or the auditory brain stem [4].

On the basis of onset, hearing loss can be prelingual or postlingual. Prelingual hearing loss occurs during infancy, before the development of speech. Postlingual hearing loss appears after normal speech development; either during childhood or adulthood. Hearing of an individual is measured in decibels (dB HL). A normal hearing threshold is 15 dB HL while a disabling hearing loss is defined as a threshold of 35 db HL or above for the better hearing ear. Hearing loss is divided into five types on the basis of severity [4]: mild hearing loss (hearing threshold 26–40 dB HL), moderate hearing loss (hearing threshold 41–55 dB), moderately severe hearing loss (hearing threshold 56–70 dB), severe hearing loss (hearing threshold 71–90 dB), and profound hearing loss (hearing threshold >90 dB). The extent of hearing loss may be stable throughout a person’s life, or it may progress and worsen over time. Genetic hearing loss contributes to at least 50% of all deafness cases, while the remaining is attributed to environmental factors such as exposure to loud noise, infections, or ototoxic drugs [4].

1.3 Genes in hearing and deafness

Genetic deafness can be monogenic in affected individuals or may have a more complex etiology. Many proteins orchestrate human hearing, and variants in hundreds of genes have been implicated in causing deafness. Some of these genes encode structural components within the auditory system; others encode proteins necessary for the function of the ear. Variants of many genes have been reported to cause structural defects of the ear with or without hearing loss in humans [4].

Inherited hearing loss has different modes of inheritance in different families [4]. These include autosomal dominant, autosomal recessive, X-linked, or mitochondrial inheritance. The autosomal forms are more commonly encountered as compared with the other types of inheritance patterns. Most of the dominantly inherited gene variants in humans cause postlingual, progressive, moderate to severe sensorineural hearing loss. In contrast, the majority of recessively inherited variants result in prelingual severe to profound sensorineural deafness [4]. However, exceptions exist for both dominant and recessive inherited hearing loss cases in which the phenotypic pattern for recessive forms resembles that of the dominant disorders or vice versa [5].

Advertisement

2. Protein kinases

Hundreds of protein kinases are encoded in the human genome and constitute more than 2.5% of the coding genes [6]. These enzymes phosphorylate the hydroxyl groups of the target proteins at the serine/threonine residues (protein serine/threonine kinases) or act on the tyrosine residues (protein tyrosine kinases) or both (dual-specificity kinases). Generally, nonreceptor kinases are intracellular cytoplasmic or nuclear proteins. Variants of most of these genes cause hearing loss in only a subset of the affected individuals, suggesting a degree of redundancy for the function of the auditory system. One such gene is CASK; patients with CASK variants have an Intellectual developmental disorder with microcephaly and pontine and cerebellar hypoplasia syndrome, and only a few individuals also have a hearing loss [7]. Interestingly, CASK has been shown to interact with whirlin and prestin in the inner ear; [8, 9] two proteins that are vital to hearing.

Sometimes, hearing loss phenotype is not investigated or observed in mouse models for many of the genes, which are known to cause deafness in humans. In other cases, targeted disruption of a gene, for example, Cdk5, causes lethality in mice, necessitating the development of animal models with selective deletion of the gene of interest in the inner ear [10] in order to determine the effect of the absence of the protein in the auditory system. Multiple studies on mouse models with deafness have suggested that some of the kinases important for hearing have roles in the kinocilia formation or maintenance of the stereocilia [9].

2.1 Dual-specificity kinases

DYRK1A is a dual-specificity kinase, which has been implicated in individuals with mental retardation and outer ear morphological defects (Table 1). Some individuals also experience hearing loss due to DYRK1A variants [11]. DYRK1A autophosphorylates itself at both serine/threonine and tyrosine residues, and thus controls its own activity. Another dual-specificity kinase, MAP2K1 is required for activation of MAPK by phosphorylating both serine and tyrosine residues. Variants of MAP2K1 have been associated with hearing loss in a few patients diagnosed with either of two different human syndromes (Table 1), as an accompanying feature to the cardiovascular defects [12, 13].

2.2 Protein serine/threonine kinases

Protein serine/threonine kinases are the most frequent types of kinases that have been implicated to have a role in hearing (Table 1). Variants of all member genes of this group, except for MYO3A, cause syndromic deafness in humans (Table 1). In some instances, hearing loss is accompanied by ear malformations, as is the case in patients with frontometaphyseal dysplasia 2. Frontometaphyseal dysplasia 2 is caused due to variants affecting MAP3K7, and conductive or sensorineural deafness is accompanied by ear malformations [14]. For a vast majority of protein serine/threonine kinases, such as CDC42BPB, CDK8, CDK9, CDK10, CDK13, the association of hearing loss due to variants of the genes in the corresponding syndromes is based on the presence of the auditory phenotype in one or only a few individuals [15, 16, 17, 18, 19]. Therefore, some of these genetic variants links to human auditory malfunction may prove to be coincidental.

In a few cases, only particular types of variants of a gene may be associated with hearing loss. For example, patients with a heterozygous nonsense variant of PRKCG have spinocerebellar ataxia 14 with hearing loss, while patients with missense variants do not have an auditory phenotype [20]. In other instances, many individuals may be affected by hearing loss, but these only constitute up to 30% of the total patients reported to have a particular syndrome due to the corresponding gene variants. For example, Coffin-Lowry Syndrome is a disorder in which patients have mental retardation, skeletal defects, and movement disorders with or without hearing loss. It is caused as a result of RPS6KA3 variants [21].

The variants of MAPKAPK5 [22], PRKCB [23], and BRAF [24] have been reported to cause hearing loss in humans, but not in mice. Variants of some protein serine/threonine kinases such as RAF1 [25] and MAP3K20 [26] cause hearing loss in humans, and their orthologous genes have a demonstrated role in mouse audition as well [26, 27]. In other cases, importance of a gene to mammalian hearing can only be gauged due to the observed phenotype in mouse models. For example, pathogenic alleles of Map3k1 [28, 29], Map3k4 [30], Pak1 [31], and Stk11 [32] are reported to cause hearing loss in mice only. Mice with Mapk1 deletion in the inner ear undergo noise-induced hearing loss [33]. However, deafness has not been reported as yet in humans, but patients with MAPK1 variants have outer ear morphological defects [34].

An interesting example of a protein serine/threonine kinase is MYO3A since it has both a C-terminal motor domain and an N-terminal kinase domain. Its loss of function variants usually cause recessively inherited moderate to severe nonsyndromic hearing loss, which can be adult onset and progressive in nature [5]. One homozygous variant abolishes MYO3A kinase function, and the affected individuals have profound deafness [35]. Dominantly inherited MYO3A variants are very rare. Of the latter, a heterozygous missense variant affecting the kinase domain was reported to cause hearing loss in affected individuals of a German family [36]. The MYO3A kinase activity may be important for phosphorylation of its own motor domain, thus reducing motor activity and regulating protein concentration in the stereocilia [37]. Different mice models homozygous for a knock-in nonsense variant or a missense variant in the kinase domain have progressive hearing loss [38, 39], mimicking the phenotype observed in humans.

2.3 Protein tyrosine kinases, nonreceptor type

So far variants in two different genes encoding nonreceptor protein tyrosine kinases, ABL1 and BTK, have been reported to cause hearing loss in some patients with different syndromes. Variants of ABL1 cause a syndromic disorder (Table 1) in which subsets of patients have outer ear abnormalities and hearing loss [40]. Recently, variants were reported in patients with a phenotype termed as ABL1 malformation syndrome, and it was shown that hearing loss in the patients occurred due to the increased tyrosine kinase activity of the protein [41]. Variants of BTK have been reported to cause otitis media and hearing loss in a few patients with agammaglobulinemia, X-linked 1, a disorder of B-lymphocyte maturation [42].

Advertisement

3. Protein phosphatases

As compared the large number of kinases, the phosphatases comprise less than 1% of the human coding genes [43]. The phosphatase enzymes dephosphorylate target proteins at the serine or threonine residues (protein serine/threonine phosphatases), while some act on the tyrosine residues (protein tyrosine phosphatases) or both tyrosine and serine/threonine residues (dual-specificity phosphatases). The protein serine/threonine phosphatases are divided into three structurally related groups while all members of protein tyrosine phosphatases and dual-specificity phosphatases belong to one structurally related class. The, atypical protein phosphatases constitute a separate group, with structural features different from the other types [44]. In contrast to the protein kinases, research has identified far fewer protein phosphatases, which have an important role in the auditory system (Table 1). These enzymes are important for disparate developmental processes, and the targeted deletions of the pertinent genes in mice have revealed their contributions to the development of ear and maintenance of hearing. In some cases, although the phosphatase itself may not have been directly implicated yet in a human hearing loss disorder, variants in their substrate or docking proteins do cause deafness [45].

3.1 Atypical protein phosphatases

The atypical protein phosphatases have an N-terminal threonine phosphatase and a C-terminal tyrosine phosphatase domain [44]. EYA1 and EYA4 are two atypical protein phosphatases that are important for hearing. Variants of EYA1 cause two allelic syndromes in humans, which include hearing loss as one of the manifestations, along with multiple outer and inner ear structural defects [46, 47]. Homozygous Eya1 mutant mice lack ears, which suggest an essential role of the encoded protein in early development [48]. Similarly, EYA4 is essential for maintenance of hearing in humans [49, 50] and mice [51]. EYA4 is one of the very few phosphatases, variants of which cause nonsyndromic deafness in humans [49], although some of its variants also give rise to a syndromic form of deafness with dilated cardiomyopathy [50].

3.2 Dual-specificity phosphatases

Dual-specificity phosphatases can catalyze the removal of phosphates from both phosphorylated tyrosine and serine/threonine residues of the target proteins. They are structurally similar to the tyrosine phosphatase family enzymes. CDC14A is a dual-specificity phosphatase and has been shown to be absolutely necessary for hearing in both humans [52, 53] and mice [53]. Moreover, some variants cause hearing loss with immotile sperm in humans and mice [53]. Most phospho protein targets of CDC14A are unknown, though drebrin (DBE1) has been proposed to be one such protein [54]. Two other dual-specificity phosphatases, DUSP1 [55, 56] and DUSP6 [57], are important for hearing in mice. Dusp1 knockout mouse mutants manifest a progressive hearing loss [56], perhaps due to disruption of cytokines [55]. Similarly, DUSP6 is required for ear development in mice [58]. Few patients with hypogonadotropic hypogonadism 19 with or without anosmia may have a hearing loss due to DUSP6 variants [59].

One unusual dual-specific protein phosphatase is PTEN, which has both lipid phosphatase and dual-specific protein phosphatase activities. Although lipid dephosphorylation by PTEN is well studied, that of protein dephosphorylation is less so. However, it was shown that PTEN plays a role in ciliogenesis by phosphorylating the protein DVL2 [60]. Heterozygous knockout Pten+/− mice have inner ear abnormalities [61] while the inner ear specific homozygous knockout mice are deaf [62] and have supernumerary hair cells [63]. In humans, some patients with Cowden syndrome have a hearing loss due to PTEN variants [64].

3.3 Protein tyrosine phosphatases nonreceptor type

Variants of protein tyrosine phosphatase PTPN11 cause two autosomal dominant syndromes (Table 1) in which patients can have hearing loss with multiple other disorders including cardiovascular manifestations [65, 66]. Sometimes, hearing loss is presented as the first symptom of the syndrome [67], while other individuals exhibit only the auditory phenotype as a nonsyndromic case [68]. Studies in HEK293 cells have demonstrated that PTPN11 variants involved in human disorders affect dephosphorylation of GAB1 [69]; another protein that is important for hearing [70].

Advertisement

4. Conclusions and perspectives

Kinases and phosphatases serve as important regulators of cell signaling and protein function within the auditory system. Many of these enzymes are required for the maintenance of inner ear structures by regulating function of different proteins, which are known to be present in the hair cells. Not only are the malfunctions of these enzymes involved in genetic hearing loss, but many environmental factors such as exposure to loud noise and oxidative stress also activate or affect the phosphorylation pathways [71]. Due to the importance of MAPK pathway to hearing [71, 72], it is a target for design of treatment of hearing loss. Pharmacological inhibitors of phosphorylation pathways are being explored for treatment of hearing loss [2]. Inhibitors are specifically developed and administered to model organisms for stopping ototoxic effects of medicinal drugs [73]. For example, direct BRAF inhibition, by dabrafenib given orally, was demonstrated to protect mouse hearing loss induced due to cisplatin administration [74]. Intra-tympanic injections for treatment of noise-induced hearing loss in model organisms are also being explored and may open up avenues for effective localized therapies in humans as well [75]. Continued research on protein phosphorylation will yield additional information on other important kinases and phosphatases and their target proteins required for human hearing and will advance our understanding of the auditory system.

Advertisement

Acknowledgments

The author thanks Ayesha Imtiaz for suggesting this topic for review and her help during the initial phases of the work.

References

  1. 1. Mateo Sanchez S, Freeman SD, Delacroix L, Malgrange B. The role of post-translational modifications in hearing and deafness. Cellular and Molecular Life Sciences. 2016;73(18):3521-3533
  2. 2. Ardito F, Giuliani M, Perrone D, Troiano G, Lo Muzio L. The crucial role of protein phosphorylation in cell signaling and its use as targeted therapy (review). International Journal of Molecular Medicine. 2017;40(2):271-280
  3. 3. Naz S, Friedman TB. Growth factor and receptor malfunctions associated with human genetic deafness. Clinical Genetics. 2020;97(1):138-155
  4. 4. Kochhar A, Hildebrand MS, Smith RJ. Clinical aspects of hereditary hearing loss. Genetics in Medicine. 2007;9(7):393-408
  5. 5. Walsh T, Walsh V, Vreugde S, Hertzano R, Shahin H, Haika S, et al. From flies’ eyes to our ears: Mutations in a human class III myosin cause progressive nonsyndromic hearing loss DFNB30. Proceedings of the National Academy of Sciences of the United States of America. 2002;99(11):7518-7523
  6. 6. Manning G, Whyte DB, Martinez R, Hunter T, Sudarsanam S. The protein kinase complement of the human genome. Science. 2002;298(5600):1912-1934
  7. 7. Burglen L, Chantot-Bastaraud S, Garel C, Milh M, Touraine R, Zanni G, et al. Spectrum of pontocerebellar hypoplasia in 13 girls and boys with CASK mutations: Confirmation of a recognizable phenotype and first description of a male mosaic patient. Orphanet Journal of Rare Diseases. 2012;7:18
  8. 8. Cimerman J, Waldhaus J, Harasztosi C, Duncker SV, Dettling J, Heidrych P, et al. Generation of somatic electromechanical force by outer hair cells may be influenced by prestin-CASK interaction at the basal junction with the Deiter’s cell. Histochemistry and Cell Biology. 2013;140(2):119-135
  9. 9. Zhu Y, Delhommel F, Cordier F, Luchow S, Mechaly A, Colcombet-Cazenave B, et al. Deciphering the unexpected binding capacity of the third PDZ domain of Whirlin to various Cochlear hair cell partners. Journal of Molecular Biology. 2020;432(22):5920-5937
  10. 10. Zhai X, Liu C, Zhao B, Wang Y, Xu Z. Inactivation of cyclin-dependent kinase 5 in hair cells causes hearing loss in mice. Frontiers in Molecular Neuroscience. 2018;11:461
  11. 11. Meissner LE, Macnamara EF, D’Souza P, Yang J, Vezina G, Ferreira CR, et al. DYRK1A pathogenic variants in two patients with syndromic intellectual disability and a review of the literature. Molecular Genetics & Genomic Medicine. 2020;8(12):e1544
  12. 12. Nishi E, Mizuno S, Nanjo Y, Niihori T, Fukushima Y, Matsubara Y, et al. A novel heterozygous MAP2K1 mutation in a patient with Noonan syndrome with multiple lentigines. American Journal of Medical Genetics. Part A. 2015;167A(2):407-411
  13. 13. Kosztyla-Hojna B, Borys J, Zdrojkowski M, Duchnowska E, Kraszewska A, Wasilewska D, et al. Phoniatric, audiological, Orodental and speech problems in a boy with cardio-Facio-cutaneous syndrome type 3 (CFC 3) due to a pathogenic variant in MAP2K1 - case study. The Application of Clinical Genetics. 2021;14:389-398
  14. 14. Le Goff C, Rogers C, Le Goff W, Pinto G, Bonnet D, Chrabieh M, et al. Heterozygous mutations in MAP3K7, encoding TGF-beta-activated kinase 1, cause Cardiospondylocarpofacial syndrome. American Journal of Human Genetics. 2016;99(2):407-413
  15. 15. Chilton I, Okur V, Vitiello G, Selicorni A, Mariani M, Goldenberg A, et al. De novo heterozygous missense and loss-of-function variants in CDC42BPB are associated with a neurodevelopmental phenotype. American Journal of Medical Genetics. Part A. 2020;182(5):962-973
  16. 16. Calpena E, Hervieu A, Kaserer T, Swagemakers SMA, Goos JAC, Popoola O, et al. De novo missense substitutions in the gene encoding CDK8, a regulator of the mediator complex, cause a syndromic developmental disorder. American Journal of Human Genetics. 2019;104(4):709-720
  17. 17. Nishina S, Hosono K, Ishitani S, Kosaki K, Yokoi T, Yoshida T, et al. Biallelic CDK9 variants as a cause of a new multiple-malformation syndrome with retinal dystrophy mimicking the CHARGE syndrome. Journal of Human Genetics. 2021;66(10):1021-1027
  18. 18. Guen VJ, Edvardson S, Fraenkel ND, Fattal-Valevski A, Jalas C, Anteby I, et al. A homozygous deleterious CDK10 mutation in a patient with agenesis of corpus callosum, retinopathy, and deafness. American Journal of Medical Genetics. Part A. 2018;176(1):92-98
  19. 19. Acharya A, Raza SI, Anwar MZ, Bharadwaj T, Liaqat K, Khokhar MAS, et al. Wolfram-like syndrome with bicuspid aortic valve due to a homozygous missense variant in CDK13. Journal of Human Genetics. 2021;66(10):1009-1018
  20. 20. Shirafuji T, Shimazaki H, Miyagi T, Ueyama T, Adachi N, Tanaka S, et al. Spinocerebellar ataxia type 14 caused by a nonsense mutation in the PRKCG gene. Molecular and Cellular Neurosciences. 2019;98:46-53
  21. 21. Pereira PM, Schneider A, Pannetier S, Heron D, Hanauer A. Coffin-Lowry syndrome. European Journal of Human Genetics. 2010;18(6):627-633
  22. 22. Horn D, Fernandez-Nunez E, Gomez-Carmona R, Rivera-Barahona A, Nevado J, Schwartzmann S, et al. Biallelic truncating variants in MAPKAPK5 cause a new developmental disorder involving neurological, cardiac, and facial anomalies combined with synpolydactyly. Genetics in Medicine. 2021;23(4):679-688
  23. 23. Martin-Sierra C, Requena T, Frejo L, Price SD, Gallego-Martinez A, Batuecas-Caletrio A, et al. A novel missense variant in PRKCB segregates low-frequency hearing loss in an autosomal dominant family with Meniere’s disease. Human Molecular Genetics. 2016;25(16):3407-3415
  24. 24. Schulz AL, Albrecht B, Arici C, van der Burgt I, Buske A, Gillessen-Kaesbach G, et al. Mutation and phenotypic spectrum in patients with cardio-facio-cutaneous and Costello syndrome. Clinical Genetics. 2008;73(1):62-70
  25. 25. Pandit B, Sarkozy A, Pennacchio LA, Carta C, Oishi K, Martinelli S, et al. Gain-of-function RAF1 mutations cause Noonan and LEOPARD syndromes with hypertrophic cardiomyopathy. Nature Genetics. 2007;39(8):1007-1012
  26. 26. Spielmann M, Kakar N, Tayebi N, Leettola C, Nurnberg G, Sowada N, et al. Exome sequencing and CRISPR/Cas genome editing identify mutations of ZAK as a cause of limb defects in humans and mice. Genome Research. 2016;26(2):183-191
  27. 27. de Iriarte RR, Magarinos M, Pfeiffer V, Rapp UR, Varela-Nieto I. C-Raf deficiency leads to hearing loss and increased noise susceptibility. Cellular and Molecular Life Sciences. 2015;72(20):3983-3998
  28. 28. Parker A, Cross SH, Jackson IJ, Hardisty-Hughes R, Morse S, Nicholson G, et al. The goya mouse mutant reveals distinct newly identified roles for MAP3K1 in the development and survival of cochlear sensory hair cells. Disease Models & Mechanisms. 2015;8(12):1555-1568
  29. 29. Yousaf R, Meng Q , Hufnagel RB, Xia Y, Puligilla C, Ahmed ZM, et al. MAP3K1 function is essential for cytoarchitecture of the mouse organ of Corti and survival of auditory hair cells. Disease Models & Mechanisms. 2015;8(12):1543-1553
  30. 30. Haque K, Pandey AK, Zheng HW, Riazuddin S, Sha SH, Puligilla C. MEKK4 signaling regulates sensory cell development and function in the mouse inner ear. The Journal of Neuroscience. 2016;36(4):1347-1361
  31. 31. Cheng C, Hou Y, Zhang Z, Wang Y, Lu L, Zhang L, et al. Disruption of the autism-related gene Pak1 causes stereocilia disorganization, hair cell loss, and deafness in mice. Journal of Genetics and Genomics. 2021;48(4):324-332
  32. 32. Men Y, Zhang A, Li H, Zhang T, Jin Y, Zhang J, et al. LKB1 is required for the development and maintenance of Stereocilia in inner ear hair cells in mice. PLoS One. 2015;10(8):e0135841
  33. 33. Kurioka T, Matsunobu T, Satoh Y, Niwa K, Endo S, Fujioka M, et al. ERK2 mediates inner hair cell survival and decreases susceptibility to noise-induced hearing loss. Scientific Reports. 2015;5:16839
  34. 34. Motta M, Pannone L, Pantaleoni F, Bocchinfuso G, Radio FC, Cecchetti S, et al. Enhanced MAPK1 function causes a neurodevelopmental disorder within the RASopathy clinical Spectrum. American Journal of Human Genetics. 2020;107(3):499-513
  35. 35. Souissi A, Abdelmalek Driss D, Chakchouk I, Ben Said M, Ben Ayed I, Mosrati MA, et al. Molecular insights into MYO3A kinase domain variants explain variability in both severity and progression of DFNB30 hearing impairment. Journal of Biomolecular Structure & Dynamics. 2021;20(1):1-12
  36. 36. Doll J, Hofrichter MAH, Bahena P, Heihoff A, Segebarth D, Muller T, et al. A novel missense variant in MYO3A is associated with autosomal dominant high-frequency hearing loss in a German family. Molecular Genetics & Genomic Medicine. 2020;8(8):e1343
  37. 37. Quintero OA, Unrath WC, Stevens SM Jr, Manor U, Kachar B, Yengo CM. Myosin 3A kinase activity is regulated by phosphorylation of the kinase domain activation loop. The Journal of Biological Chemistry. 2013;288(52):37126-37137
  38. 38. Li P, Wen Z, Zhang G, Zhang A, Fu X, Gao J. Knock-In mice with Myo3a Y137C mutation displayed progressive hearing loss and hair cell degeneration in the inner ear. Neural Plasticity. 2018;2018:4372913
  39. 39. Walsh VL, Raviv D, Dror AA, Shahin H, Walsh T, Kanaan MN, et al. A mouse model for human hearing loss DFNB30 due to loss of function of myosin IIIA. Mammalian Genome. 2011;22(3-4):170-177
  40. 40. Chen CA, Crutcher E, Gill H, Nelson TN, Robak LA, Jongmans MCJ, et al. The expanding clinical phenotype of germline ABL1-associated congenital heart defects and skeletal malformations syndrome. Human Mutation. 2020;41(10):1738-1744
  41. 41. Blakes AJM, Gaul E, Lam W, Shannon N, Knapp KM, Bicknell LS, et al. Pathogenic variants causing ABL1 malformation syndrome cluster in a myristoyl-binding pocket and increase tyrosine kinase activity. European Journal of Human Genetics. 2021;29(4):593-603
  42. 42. Berlucchi M, Soresina A, Redaelli De Zinis LO, Valetti L, Valotti R, Lougaris V, et al. Sensorineural hearing loss in primary antibody deficiency disorders. The Journal of Pediatrics. 2008;153(2):293-296
  43. 43. Chen MJ, Dixon JE, Manning G. Genomics and evolution of protein phosphatases. Science Signaling. 2017;10(474):eaag1796
  44. 44. Sadatomi D, Tanimura S, Ozaki K, Takeda K. Atypical protein phosphatases: Emerging players in cellular signaling. International Journal of Molecular Sciences. 2013;14(3):4596-4612
  45. 45. Ferrar T, Chamousset D, De Wever V, Nimick M, Andersen J, Trinkle-Mulcahy L, et al. Taperin (c9orf75), a mutated gene in nonsyndromic deafness, encodes a vertebrate specific, nuclear localized protein phosphatase one alpha (PP1alpha) docking protein. Biology Open. 2012;1(2):128-139
  46. 46. Abdelhak S, Kalatzis V, Heilig R, Compain S, Samson D, Vincent C, et al. A human homologue of the drosophila eyes absent gene underlies branchio-Oto-renal (BOR) syndrome and identifies a novel gene family. Nature Genetics. 1997;15(2):157-164
  47. 47. Vincent C, Kalatzis V, Abdelhak S, Chaib H, Compain S, Helias J, et al. BOR and BO syndromes are allelic defects of EYA1. European Journal of Human Genetics. 1997;5(4):242-246
  48. 48. Xu PX, Adams J, Peters H, Brown MC, Heaney S, Maas R. Eya1-deficient mice lack ears and kidneys and show abnormal apoptosis of organ primordia. Nature Genetics. 1999;23(1):113-117
  49. 49. Wayne S, Robertson NG, DeClau F, Chen N, Verhoeven K, Prasad S, et al. Mutations in the transcriptional activator EYA4 cause late-onset deafness at the DFNA10 locus. Human Molecular Genetics. 2001;10(3):195-200
  50. 50. Schonberger J, Wang L, Shin JT, Kim SD, Depreux FF, Zhu H, et al. Mutation in the transcriptional coactivator EYA4 causes dilated cardiomyopathy and sensorineural hearing loss. Nature Genetics. 2005;37(4):418-422
  51. 51. Depreux FF, Darrow K, Conner DA, Eavey RD, Liberman MC, Seidman CE, et al. Eya4-deficient mice are a model for heritable otitis media. The Journal of Clinical Investigation. 2008;118(2):651-658
  52. 52. Delmaghani S, Aghaie A, Bouyacoub Y, El Hachmi H, Bonnet C, Riahi Z, et al. Mutations in CDC14A, encoding a protein phosphatase involved in hair cell Ciliogenesis, cause autosomal-recessive severe to profound deafness. American Journal of Human Genetics. 2016;98(6):1266-1270
  53. 53. Imtiaz A, Belyantseva IA, Beirl AJ, Fenollar-Ferrer C, Bashir R, Bukhari I, et al. CDC14A phosphatase is essential for hearing and male fertility in mouse and human. Human Molecular Genetics. 2018;27(5):780-798
  54. 54. Uddin B, Partscht P, Chen NP, Neuner A, Weiss M, Hardt R, et al. The human phosphatase CDC14A modulates primary cilium length by regulating centrosomal actin nucleation. EMBO Reports. 2019;20(1):e46544
  55. 55. Bermudez-Munoz JM, Celaya AM, Garcia-Mato A, Munoz-Espin D, Rodriguez-de la Rosa L, Serrano M, et al. Dual-specificity phosphatase 1 (DUSP1) has a central role in redox homeostasis and inflammation in the mouse cochlea. Antioxidants (Basel). 2021;10(9):1351
  56. 56. Celaya AM, Sanchez-Perez I, Bermudez-Munoz JM, Rodriguez-de la Rosa L, Pintado-Berninches L, Perona R, et al. Deficit of mitogen-activated protein kinase phosphatase 1 (DUSP1) accelerates progressive hearing loss. eLife. 2019;8:e39159
  57. 57. Li C, Scott DA, Hatch E, Tian X, Mansour SL. Dusp6 (Mkp3) is a negative feedback regulator of FGF-stimulated ERK signaling during mouse development. Development. 2007;134(1):167-176
  58. 58. Urness LD, Li C, Wang X, Mansour SL. Expression of ERK signaling inhibitors Dusp6, Dusp7, and Dusp9 during mouse ear development. Developmental Dynamics. 2008;237(1):163-169
  59. 59. Miraoui H, Dwyer AA, Sykiotis GP, Plummer L, Chung W, Feng B, et al. Mutations in FGF17, IL17RD, DUSP6, SPRY4, and FLRT3 are identified in individuals with congenital hypogonadotropic hypogonadism. American Journal of Human Genetics. 2013;92(5):725-743
  60. 60. Shnitsar I, Bashkurov M, Masson GR, Ogunjimi AA, Mosessian S, Cabeza EA, et al. PTEN regulates cilia through Dishevelled. Nature Communications. 2015;6:8388
  61. 61. Dong Y, Sui L, Yamaguchi F, Kamitori K, Hirata Y, Hossain MA, et al. Phosphatase and tensin homolog deleted on chromosome 10 regulates sensory cell proliferation and differentiation of hair bundles in the mammalian cochlea. Neuroscience. 2010;170(4):1304-1313
  62. 62. Kim HJ, Woo HM, Ryu J, Bok J, Kim JW, Choi SB, et al. Conditional deletion of pten leads to defects in nerve innervation and neuronal survival in inner ear development. PLoS One. 2013;8(2):e55609
  63. 63. Sun C, Zhao J, Jin Y, Hou C, Zong W, Lu T, et al. PTEN regulation of the proliferation and differentiation of auditory progenitors through the PTEN/PI3K/Akt-signaling pathway in mice. Neuroreport. 2014;25(3):177-183
  64. 64. Taylor A, Delon I, Allinson K, Trotman J, Liu H, Abbs S, et al. Malignant peripheral nerve sheath tumor in cowden syndrome: A first report. Journal of Neuropathology and Experimental Neurology. 2015;74(4):288-292
  65. 65. Yoshida R, Nagai T, Hasegawa T, Kinoshita E, Tanaka T, Ogata T. Two novel and one recurrent PTPN11 mutations in LEOPARD syndrome. American Journal of Medical Genetics. Part A. 2004;130A(4):432-434
  66. 66. Tartaglia M, Mehler EL, Goldberg R, Zampino G, Brunner HG, Kremer H, et al. Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome. Nature Genetics. 2001;29(4):465-468
  67. 67. Gao X, Huang SS, Qiu SW, Su Y, Wang WQ , Xu HY, et al. Congenital sensorineural hearing loss as the initial presentation of PTPN11-associated Noonan syndrome with multiple lentigines or Noonan syndrome: Clinical features and underlying mechanisms. Journal of Medical Genetics. 2021;58(7):465-474
  68. 68. Bademci G, Cengiz FB, Foster Ii J, Duman D, Sennaroglu L, Diaz-Horta O, et al. Variations in multiple syndromic deafness genes mimic non-syndromic hearing loss. Scientific Reports. 2016;6:31622
  69. 69. Edouard T, Combier JP, Nedelec A, Bel-Vialar S, Metrich M, Conte-Auriol F, et al. Functional effects of PTPN11 (SHP2) mutations causing LEOPARD syndrome on epidermal growth factor-induced phosphoinositide 3-kinase/AKT/glycogen synthase kinase 3beta signaling. Molecular and Cellular Biology. 2010;30(10):2498-2507
  70. 70. Yousaf R, Ahmed ZM, Giese AP, Morell RJ, Lagziel A, Dabdoub A, et al. Modifier variant of METTL13 suppresses human GAB1-associated profound deafness. The Journal of Clinical Investigation. 2018;128(4):1509-1522
  71. 71. Liu Y, Wei M, Mao X, Chen T, Lin P, Wang W. Key signaling pathways regulate the development and survival of auditory hair cells. Neural Plasticity. 2021;2021:5522717
  72. 72. Alagramam KN, Stepanyan R, Jamesdaniel S, Chen DH, Davis RR. Noise exposure immediately activates cochlear mitogen-activated protein kinase signaling. Noise & Health. 2014;16(73):400-409
  73. 73. Hazlitt RA, Teitz T, Bonga JD, Fang J, Diao S, Iconaru L, et al. Development of second-generation CDK2 inhibitors for the prevention of cisplatin-induced hearing loss. Journal of Medicinal Chemistry. 2018;61(17):7700-7709
  74. 74. Ingersoll MA, Malloy EA, Caster LE, Holland EM, Xu Z, Zallocchi M, et al. BRAF inhibition protects against hearing loss in mice. Science Advances. 2020;6(49):eabd0561
  75. 75. Rybak LP, Dhukhwa A, Mukherjea D, Ramkumar V. Local drug delivery for prevention of hearing loss. Frontiers in Cellular Neuroscience. 2019;13:300

Written By

Sadaf Naz

Submitted: 14 March 2022 Reviewed: 16 May 2022 Published: 13 July 2022

© 2022 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution 3.0 License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Continue reading from the same book

View All
Chapter 8 Issues in Creation of Bio-Compatible Cochlear Sign...

By Wlodzimierz (“Vlad”) Wojcik

127 downloads

Chapter 9 Hearing Restoration through Optical Wireless Cochl...

By Stylianos E. Trevlakis, Alexandros-Apostolos A. Bo...

261 downloads

Chapter 1 Structure and Physiology of Human Ear Involved in ...

By Alishbah Sheikh, Bint-e-Zainab, Kanwal Shabbir an...

1143 downloads

Your cart

Discounts available on purchase of multiple copies. View rates

Subtotal £0.00

Local taxes (VAT) are calculated in later steps, if applicable.

Support: orders@intechopen.com