Dataset Information

Calpain-10 regulates actin dynamics by proteolysis of microtubule-associated protein 1B.

ABSTRACT: Calpain-10 (CAPN10) is the calpain family protease identified as the first candidate susceptibility gene for type 2 diabetes mellitus (T2DM). However, the detailed molecular mechanism has not yet been elucidated. Here we report that CAPN10 processes microtubule associated protein 1 (MAP1) family proteins into heavy and light chains and regulates their binding activities to microtubules and actin filaments. Immunofluorescent analysis of Capn10-/- mouse embryonic fibroblasts shows that MAP1B, a member of the MAP1 family of proteins, is localized at actin filaments rather than at microtubules. Furthermore, fluorescence recovery after photo-bleaching analysis shows that calpain-10 regulates actin dynamics via MAP1B cleavage. Moreover, in pancreatic islets from CAPN10 knockout mice, insulin secretion was significantly increased both at the high and low glucose levels. These findings indicate that deficiency of calpain-10 expression may affect insulin secretion by abnormal actin reorganization, coordination and dynamics through MAP1 family processing.

SUBMITTER: Hatta T

PROVIDER: S-EPMC6233169 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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Calpain-10 regulates actin dynamics by proteolysis of microtubule-associated protein 1B.

Hatta Tomohisa T Iemura Shun-Ichiro SI Ohishi Tomokazu T Nakayama Hiroshi H Seimiya Hiroyuki H Yasuda Takao T Iizuka Katsumi K Fukuda Mitsunori M Takeda Jun J Natsume Tohru T Horikawa Yukio Y

Scientific reports 20181113 1

Calpain-10 (CAPN10) is the calpain family protease identified as the first candidate susceptibility gene for type 2 diabetes mellitus (T2DM). However, the detailed molecular mechanism has not yet been elucidated. Here we report that CAPN10 processes microtubule associated protein 1 (MAP1) family proteins into heavy and light chains and regulates their binding activities to microtubules and actin filaments. Immunofluorescent analysis of Capn10<sup>-/-</sup> mouse embryonic fibroblasts shows that ...[more]

PMID: 30425305

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Project description:Guidance of axons to their proper synaptic target sites requires spatially and temporally precise modulation of biochemical signals within growth cones. Ionic calcium (Ca2+) is an essential signal for axon guidance that mediates opposing effects on growth cone motility. The diverse effects of Ca2+ arise from the precise localization of Ca2+ signals into microdomains containing specific Ca2+ effectors. For example, differences in the mechanical and chemical composition of the underlying substrata elicit local Ca2+ signals within growth cone filopodia that regulate axon guidance through activation of the protease calpain. However, how calpain regulates growth cone motility remains unclear. Here, we identify the adhesion proteins talin and focal adhesion kinase (FAK) as proteolytic targets of calpain in Xenopus laevis spinal cord neurons both in vivo and in vitro Inhibition of calpain increases the localization of endogenous adhesion signaling to growth cone filopodia. Using live cell microscopy and specific calpain-resistant point-mutants of talin (L432G) and FAK (V744G), we find that calpain inhibits paxillin-based adhesion assembly through cleavage of talin and FAK, and adhesion disassembly through cleavage of FAK. Blocking calpain cleavage of talin and FAK inhibits repulsive turning from focal uncaging of Ca2+ within filopodia. In addition, blocking calpain cleavage of talin and FAK in vivo promotes Rohon-Beard peripheral axon extension into the skin. These data demonstrate that filopodial Ca2+ signals regulate axon outgrowth and guidance through calpain regulation of adhesion dynamics through specific cleavage of talin and FAK.SIGNIFICANCE STATEMENT The proper formation of neuronal networks requires accurate guidance of axons and dendrites during development by motile structures known as growth cones. Understanding the intracellular signaling mechanisms that govern growth cone motility will clarify how the nervous system develops and regenerates, and may identify areas of therapeutic intervention in disease or injury. One important signal that controls growth cones is that of local Ca2+ transients, which control the rate and direction of axon outgrowth. We demonstrate here that Ca2+-dependent inhibition axon outgrowth and guidance is mediated by calpain proteolysis of the adhesion proteins talin and focal adhesion kinase. Our findings provide mechanistic insight into Ca2+/calpain regulation of growth cone motility and axon guidance during neuronal development.

Dataset Information

Calpain-10 regulates actin dynamics by proteolysis of microtubule-associated protein 1B.

Publications

Calpain-10 regulates actin dynamics by proteolysis of microtubule-associated protein 1B.

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