Binding of laminin α1-chain LG4-5 domain to α-dystroglycan causes tyrosine phosphorylation of syntrophin to initiate Rac1 signaling

Yan Wen Zhou, Donald Thomason, Donald Gullberg, Harry W. Jarrett

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

Previously, a signaling pathway was described [Oak, Zhou, and Jarrett (2003) J. Biol. Chem. 278, 39287-39295] that links matrix laminin binding on the outside of the sarcolemma to Grb2 binding to syntrophin on the inside surface of the sarcolemma and by way of Grb2-Sos1-Rac1-PAK1-JNK ultimately results in the phosphorylation of c-jun on Ser65. How this signaling is initiated was investigated. Grb2-binding to syntrophin is increased by the addition of either laminin-1 or the isolated laminin α1 globular domain modules LG4-5, a protein referred to as E3. This identifies the LG4-5 sequences as the region of laminin responsible for signaling. Since laminin α1 LG4 is known to bind α-dystroglycan, this directly implicates α-dystroglycan as the laminin-signaling receptor. E3 or laminin-1 increase Grb2-binding and Rac1 activation. In the presence of E3 or laminin-1, syntrophin is phosphorylated on a tyrosine residue, and this increases and alters Grb2 binding. The α-dystroglycan antibody, IIH6, which blocks binding of laminins to α-dystroglycan, blocks both the laminin-induced Sos1/2 recruitment and syntrophin phosphorylation, showing that it is α-dystroglycan binding the LG4-5 region of laminin that is responsible. The C-terminal SH3 domain of Grb2 (C-SH3) binds only to nonphosphorylated syntrophin, and phosphorylation causes the Grb2 SH2 domain to bind and prevents SH3 binding. Syntrophin, tyrosine phosphate, β-dystroglycan, and Rac1 all co-localize to the sarcolemma of rat muscle sections. A model for how this phosphorylation may initiate downstream events in laminin signaling is presented.

Original languageEnglish (US)
Pages (from-to)2042-2052
Number of pages11
JournalBiochemistry
Volume45
Issue number7
DOIs
StatePublished - Feb 21 2006

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Dystroglycans
Phosphorylation
Laminin
Tyrosine
Sarcolemma
src Homology Domains
Laminin Receptors
laminin 1
syntrophin
Muscle
Phosphates
Rats
Chemical activation
Muscles
Antibodies

All Science Journal Classification (ASJC) codes

  • Biochemistry

Cite this

Binding of laminin α1-chain LG4-5 domain to α-dystroglycan causes tyrosine phosphorylation of syntrophin to initiate Rac1 signaling. / Zhou, Yan Wen; Thomason, Donald; Gullberg, Donald; Jarrett, Harry W.

In: Biochemistry, Vol. 45, No. 7, 21.02.2006, p. 2042-2052.

Research output: Contribution to journalArticle

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abstract = "Previously, a signaling pathway was described [Oak, Zhou, and Jarrett (2003) J. Biol. Chem. 278, 39287-39295] that links matrix laminin binding on the outside of the sarcolemma to Grb2 binding to syntrophin on the inside surface of the sarcolemma and by way of Grb2-Sos1-Rac1-PAK1-JNK ultimately results in the phosphorylation of c-jun on Ser65. How this signaling is initiated was investigated. Grb2-binding to syntrophin is increased by the addition of either laminin-1 or the isolated laminin α1 globular domain modules LG4-5, a protein referred to as E3. This identifies the LG4-5 sequences as the region of laminin responsible for signaling. Since laminin α1 LG4 is known to bind α-dystroglycan, this directly implicates α-dystroglycan as the laminin-signaling receptor. E3 or laminin-1 increase Grb2-binding and Rac1 activation. In the presence of E3 or laminin-1, syntrophin is phosphorylated on a tyrosine residue, and this increases and alters Grb2 binding. The α-dystroglycan antibody, IIH6, which blocks binding of laminins to α-dystroglycan, blocks both the laminin-induced Sos1/2 recruitment and syntrophin phosphorylation, showing that it is α-dystroglycan binding the LG4-5 region of laminin that is responsible. The C-terminal SH3 domain of Grb2 (C-SH3) binds only to nonphosphorylated syntrophin, and phosphorylation causes the Grb2 SH2 domain to bind and prevents SH3 binding. Syntrophin, tyrosine phosphate, β-dystroglycan, and Rac1 all co-localize to the sarcolemma of rat muscle sections. A model for how this phosphorylation may initiate downstream events in laminin signaling is presented.",
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