Laminin-induced activation of Rac1 and JNKp46 is initiated by Src family kinases and mimics the effects of skeletal muscle contraction

Yan Wen Zhou, Daifeng Jiang, Donald Thomason, Harry W. Jarrett

Research output: Contribution to journalArticle

33 Citations (Scopus)

Abstract

Binding of laminin to dystroglycan in the dystrophin glycoprotein complex causes signaling through dystroglycan-syntrophin-grb2-SOS1-Rac1-PAK1-JNK. Laminin binding also causes syntrophin tyrosine phosphorylation to initiate signaling. The kinase responsible was investigated here. PP2 and SU6656, specific inhibitors of Src family kinases, decreased the amount of phosphotyrosine syntrophin and decreased the level of active Rac1 in laminin-treated myoblasts, myotubes, or skeletal muscle microsomes. c-Src and c-Fyn both phosphorylate syntrophin, and inhibition of either with specific siRNAs diminishes the level of syntrophin phosphorylation. When the rat gastrocnemius was contracted, the level of Rac1 activation increased compared to that of the relaxed control muscle and Rac1 colocalized with β-dystroglycan. Similar results were obtained when the muscle was stretched. Contracted muscle also contained more activated c-Jun N-terminal kinase, JNKp46. E3, an expressed protein containing only laminin domains LG4 and LG5, increased the rate of proliferation of myoblasts, and PP2 prevented cell proliferation. In addition, Src family kinases colocalized with activated Rac1 and with laminin-Sepharose in solid-phase binding assays. Thus, contraction, stretching, or laminin binding causes recruitment of Src family kinase to the dystrophin glycoprotein complex, activating Rac1 and inducing downstream signaling. The DGC likely represents a mechanoreceptor in skeletal muscle-regulating muscle growth in response to muscle activity. Src family kinases play an initiating and critical role.

Original languageEnglish (US)
Pages (from-to)14907-14916
Number of pages10
JournalBiochemistry
Volume46
Issue number51
DOIs
StatePublished - Dec 25 2007

Fingerprint

src-Family Kinases
Laminin
Muscle Contraction
Muscle
Skeletal Muscle
Chemical activation
Dystroglycans
Muscles
Dystrophin
Myoblasts
Phosphorylation
Glycoproteins
Mechanoreceptors
Phosphotyrosine
JNK Mitogen-Activated Protein Kinases
Skeletal Muscle Fibers
Microsomes
Sepharose
Cell proliferation
Tyrosine

All Science Journal Classification (ASJC) codes

  • Biochemistry

Cite this

Laminin-induced activation of Rac1 and JNKp46 is initiated by Src family kinases and mimics the effects of skeletal muscle contraction. / Zhou, Yan Wen; Jiang, Daifeng; Thomason, Donald; Jarrett, Harry W.

In: Biochemistry, Vol. 46, No. 51, 25.12.2007, p. 14907-14916.

Research output: Contribution to journalArticle

@article{820c193f5179488bb26ce75a097c785a,
title = "Laminin-induced activation of Rac1 and JNKp46 is initiated by Src family kinases and mimics the effects of skeletal muscle contraction",
abstract = "Binding of laminin to dystroglycan in the dystrophin glycoprotein complex causes signaling through dystroglycan-syntrophin-grb2-SOS1-Rac1-PAK1-JNK. Laminin binding also causes syntrophin tyrosine phosphorylation to initiate signaling. The kinase responsible was investigated here. PP2 and SU6656, specific inhibitors of Src family kinases, decreased the amount of phosphotyrosine syntrophin and decreased the level of active Rac1 in laminin-treated myoblasts, myotubes, or skeletal muscle microsomes. c-Src and c-Fyn both phosphorylate syntrophin, and inhibition of either with specific siRNAs diminishes the level of syntrophin phosphorylation. When the rat gastrocnemius was contracted, the level of Rac1 activation increased compared to that of the relaxed control muscle and Rac1 colocalized with β-dystroglycan. Similar results were obtained when the muscle was stretched. Contracted muscle also contained more activated c-Jun N-terminal kinase, JNKp46. E3, an expressed protein containing only laminin domains LG4 and LG5, increased the rate of proliferation of myoblasts, and PP2 prevented cell proliferation. In addition, Src family kinases colocalized with activated Rac1 and with laminin-Sepharose in solid-phase binding assays. Thus, contraction, stretching, or laminin binding causes recruitment of Src family kinase to the dystrophin glycoprotein complex, activating Rac1 and inducing downstream signaling. The DGC likely represents a mechanoreceptor in skeletal muscle-regulating muscle growth in response to muscle activity. Src family kinases play an initiating and critical role.",
author = "Zhou, {Yan Wen} and Daifeng Jiang and Donald Thomason and Jarrett, {Harry W.}",
year = "2007",
month = "12",
day = "25",
doi = "10.1021/bi701384k",
language = "English (US)",
volume = "46",
pages = "14907--14916",
journal = "Biochemistry",
issn = "0006-2960",
publisher = "American Chemical Society",
number = "51",

}

TY - JOUR

T1 - Laminin-induced activation of Rac1 and JNKp46 is initiated by Src family kinases and mimics the effects of skeletal muscle contraction

AU - Zhou, Yan Wen

AU - Jiang, Daifeng

AU - Thomason, Donald

AU - Jarrett, Harry W.

PY - 2007/12/25

Y1 - 2007/12/25

N2 - Binding of laminin to dystroglycan in the dystrophin glycoprotein complex causes signaling through dystroglycan-syntrophin-grb2-SOS1-Rac1-PAK1-JNK. Laminin binding also causes syntrophin tyrosine phosphorylation to initiate signaling. The kinase responsible was investigated here. PP2 and SU6656, specific inhibitors of Src family kinases, decreased the amount of phosphotyrosine syntrophin and decreased the level of active Rac1 in laminin-treated myoblasts, myotubes, or skeletal muscle microsomes. c-Src and c-Fyn both phosphorylate syntrophin, and inhibition of either with specific siRNAs diminishes the level of syntrophin phosphorylation. When the rat gastrocnemius was contracted, the level of Rac1 activation increased compared to that of the relaxed control muscle and Rac1 colocalized with β-dystroglycan. Similar results were obtained when the muscle was stretched. Contracted muscle also contained more activated c-Jun N-terminal kinase, JNKp46. E3, an expressed protein containing only laminin domains LG4 and LG5, increased the rate of proliferation of myoblasts, and PP2 prevented cell proliferation. In addition, Src family kinases colocalized with activated Rac1 and with laminin-Sepharose in solid-phase binding assays. Thus, contraction, stretching, or laminin binding causes recruitment of Src family kinase to the dystrophin glycoprotein complex, activating Rac1 and inducing downstream signaling. The DGC likely represents a mechanoreceptor in skeletal muscle-regulating muscle growth in response to muscle activity. Src family kinases play an initiating and critical role.

AB - Binding of laminin to dystroglycan in the dystrophin glycoprotein complex causes signaling through dystroglycan-syntrophin-grb2-SOS1-Rac1-PAK1-JNK. Laminin binding also causes syntrophin tyrosine phosphorylation to initiate signaling. The kinase responsible was investigated here. PP2 and SU6656, specific inhibitors of Src family kinases, decreased the amount of phosphotyrosine syntrophin and decreased the level of active Rac1 in laminin-treated myoblasts, myotubes, or skeletal muscle microsomes. c-Src and c-Fyn both phosphorylate syntrophin, and inhibition of either with specific siRNAs diminishes the level of syntrophin phosphorylation. When the rat gastrocnemius was contracted, the level of Rac1 activation increased compared to that of the relaxed control muscle and Rac1 colocalized with β-dystroglycan. Similar results were obtained when the muscle was stretched. Contracted muscle also contained more activated c-Jun N-terminal kinase, JNKp46. E3, an expressed protein containing only laminin domains LG4 and LG5, increased the rate of proliferation of myoblasts, and PP2 prevented cell proliferation. In addition, Src family kinases colocalized with activated Rac1 and with laminin-Sepharose in solid-phase binding assays. Thus, contraction, stretching, or laminin binding causes recruitment of Src family kinase to the dystrophin glycoprotein complex, activating Rac1 and inducing downstream signaling. The DGC likely represents a mechanoreceptor in skeletal muscle-regulating muscle growth in response to muscle activity. Src family kinases play an initiating and critical role.

UR - http://www.scopus.com/inward/record.url?scp=37349039361&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=37349039361&partnerID=8YFLogxK

U2 - 10.1021/bi701384k

DO - 10.1021/bi701384k

M3 - Article

VL - 46

SP - 14907

EP - 14916

JO - Biochemistry

JF - Biochemistry

SN - 0006-2960

IS - 51

ER -