Perception of sound and gravity by TMC1 and TMC2

Lin, Xiaobo

doi:10.1172/jci61167

Cited by 7 publications

(7 citation statements)

References 21 publications

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“…Thus far, ≈21 different mutations have been reported and over 50 families with pre‐lingual severe‐to‐profound hearing impairments due to DFNB7/11 have been described. This is similar to the phenotype seen in TMC1 knockout mice . DFNB7/11 can also present with post‐lingual hearing impairment, as described by de Heer et al .…”

Section: Severe‐to‐profound Hearing Impairmentsupporting

confidence: 84%

Features of autosomal recessive non‐syndromic hearing impairment: a review to serve as a reference

Oonk

Huygen

Kunst

et al. 2016

Clinical Otolaryngology

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Section: Severe‐to‐profound Hearing Impairmentsupporting

confidence: 84%

Features of autosomal recessive non‐syndromic hearing impairment: a review to serve as a reference

Oonk

Huygen

Kunst

et al. 2016

Clinical Otolaryngology

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“…In the model, both expression of DUSP1 and deletion of DUSP2 are necessary for preventing the JNK apoptotic switch (as the nominal model is robust to dysregulation of either DUSP in isolation). The result is particularly interesting in the context of (a) cancer, as many cancers show increased expression of DUSP1 and reduced expression of DUSP2, and (b) tumor related conditions such as hypoxia, where low oxygen levels upregulate DUSP1 and downregulate DUSP2 (Patterson et al, 2009; Lin et al, 2011). According to our model, these conditions would prevent the JNK apoptotic switch.…”

Section: Discussionmentioning

confidence: 99%

“…According to our model, these conditions would prevent the JNK apoptotic switch. Indeed, forced expression of DUSP2 abolished hypoxia induced chemoresistance in human cancer cell lines (Lin et al, 2011), and inhibition of DUSP1 sensitized several resistant cancer cell lines to JNK dependent apoptosis (Laderoute et al, 1999; Sánchez-Pérez et al, 2000; Small et al, 2007; Wang et al, 2008). …”

Section: Discussionmentioning

confidence: 99%

Crosstalk and Signaling Switches in Mitogen-Activated Protein Kinase Cascades

et al. 2012

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Mitogen-activated protein kinase (MAPK) cascades control cell fate decisions, such as proliferation, differentiation, and apoptosis by integrating and processing intra- and extracellular cues. However, similar MAPK kinetic profiles can be associated with opposing cellular decisions depending on cell type, signal strength, and dynamics. This implies that signaling by each individual MAPK cascade has to be considered in the context of the entire MAPK network. Here, we develop a dynamic model of feedback and crosstalk for the three major MAPK cascades; extracellular signal-regulated kinase (ERK), p38 mitogen-activated protein kinase (p38), c-Jun N-terminal kinase (JNK), and also include input from protein kinase B (AKT) signaling. Focusing on the bistable activation characteristics of the JNK pathway, this model explains how pathway crosstalk harmonizes different MAPK responses resulting in pivotal cell fate decisions. We show that JNK can switch from a transient to sustained activity due to multiple positive feedback loops. Once activated, positive feedback locks JNK in a highly active state and promotes cell death. The switch is modulated by the ERK, p38, and AKT pathways. ERK activation enhances the dual specificity phosphatase (DUSP) mediated dephosphorylation of JNK and shifts the threshold of the apoptotic switch to higher inputs. Activation of p38 restores the threshold by inhibiting ERK activity via the PP1 or PP2A phosphatases. Finally, AKT activation inhibits the JNK positive feedback, thus abrogating the apoptotic switch and allowing only proliferative signaling. Our model facilitates understanding of how cancerous deregulations disturb MAPK signal processing and provides explanations for certain drug resistances. We highlight a critical role of DUSP1 and DUSP2 expression patterns in facilitating the switching of JNK activity and show how oncogene induced ERK hyperactivity prevents the normal apoptotic switch explaining the failure of certain drugs to induce apoptosis.

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“…Most have not been studied at all aside from genetic studies of disease linkage, and PCR analysis of transcript expression. The exceptions are that TMC1 and TMC2 expression in the ear has been studied in detail, TMC1 topology has been determined, and the cellular and auditory defects of df and Bth mice have been thoroughly dissected (Holt et al, 2014;Kawashima et al, 2011;Kurima et al, 2002;Lin, 2011;Marcotti, Erven, Johnson, Steel, & Kros, 2006;Pan et al, 2013;Vreugde et al, 2002). Given their expression in tissues including the auditory system, heart, brain, kidney, and colon, and association of several of the TMC genes with inherited human diseases, the eight TMC genes are likely to be of considerable importance in human physiology and disease.…”

Section: Discussionmentioning

confidence: 99%

KCNQ1 rescues TMC1 plasma membrane expression but not mechanosensitive channel activity

Harkcom

Papanikolaou

Kanda

et al. 2019

Journal Cellular Physiology

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Transmembrane channel‐like protein isoform 1 (TMC1) is essential for the generation of mechano‐electrical transducer currents in hair cells of the inner ear. TMC1 disruption causes hair cell degeneration and deafness in mice and humans. Although thought to be expressed at the cell surface in vivo, TMC1 remains in the endoplasmic reticulum when heterologously expressed in standard cell lines, precluding determination of its roles in mechanosensing and pore formation. Here, we report that the KCNQ1 Kv channel forms complexes with TMC1 and rescues its surface expression when coexpressed in Chinese Hamster Ovary cells. TMC1 rescue is specific for KCNQ1 within the KCNQ family, is prevented by a KCNQ1 trafficking‐deficient mutation, and is influenced by KCNE β subunits and inhibition of KCNQ1 endocytosis. TMC1 lowers KCNQ1 and KCNQ1‐KCNE1 K+ currents, and despite the surface expression, it does not detectably respond to mechanical stimulation or high salt. We conclude that TMC1 is not intrinsically mechano‐ or osmosensitive but has the capacity for cell surface expression, and requires partner protein(s) for surface expression and mechanosensitivity. We suggest that KCNQ1, expression of which is not thought to overlap with TMC1 in hair cells, is a proxy partner bearing structural elements or a sequence motif reminiscent of a true in vivo TMC1 hair cell partner. Discovery of the first reported strategy to rescue TMC1 surface expression should aid future studies of the TMC1 function and native partners.

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Perception of sound and gravity by TMC1 and TMC2

Cited by 7 publications

References 21 publications

Features of autosomal recessive non‐syndromic hearing impairment: a review to serve as a reference

Features of autosomal recessive non‐syndromic hearing impairment: a review to serve as a reference

Crosstalk and Signaling Switches in Mitogen-Activated Protein Kinase Cascades

KCNQ1 rescues TMC1 plasma membrane expression but not mechanosensitive channel activity

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