Binding of laminin alpha1-chain LG4-5 domain to alpha-dystroglycan causes tyrosine phosphorylation of syntrophin to initiate Rac1 signaling.

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  • Additional Information
    • Source:
      Publisher: American Chemical Society Country of Publication: United States NLM ID: 0370623 Publication Model: Print Cited Medium: Print ISSN: 0006-2960 (Print) Linking ISSN: 00062960 NLM ISO Abbreviation: Biochemistry Subsets: MEDLINE
    • Publication Information:
      Original Publication: Washington, American Chemical Society.
    • Subject Terms:
      Dystroglycans/*metabolism ; Dystrophin-Associated Proteins/*metabolism ; Laminin/*metabolism ; Tyrosine/*metabolism ; rac1 GTP-Binding Protein/*physiology; Amino Acid Sequence ; Animals ; Cells, Cultured ; Dystroglycans/immunology ; GRB2 Adaptor Protein/metabolism ; Mice ; Muscle Fibers, Skeletal/metabolism ; Myoblasts/metabolism ; Phosphorylation ; Protein Structure, Tertiary ; Rabbits ; Rats ; Sarcolemma ; Signal Transduction/drug effects ; Son of Sevenless Proteins/metabolism
    • 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 Ser(65). How this signaling is initiated was investigated. Grb2-binding to syntrophin is increased by the addition of either laminin-1 or the isolated laminin alpha1 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 alpha1 LG4 is known to bind alpha-dystroglycan, this directly implicates alpha-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 alpha-dystroglycan antibody, IIH6, which blocks binding of laminins to alpha-dystroglycan, blocks both the laminin-induced Sos1/2 recruitment and syntrophin phosphorylation, showing that it is alpha-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, beta-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.
    • Accession Number:
      0 (Dystrophin-Associated Proteins)
      0 (GRB2 Adaptor Protein)
      0 (Grb2 protein, mouse)
      0 (Laminin)
      0 (Son of Sevenless Proteins)
      0 (laminin 1)
      0 (syntrophin)
      146888-27-9 (Dystroglycans)
      42HK56048U (Tyrosine)
      EC 3.6.5.2 (rac1 GTP-Binding Protein)
    • Publication Date:
      Date Created: 20060216 Date Completed: 20060410 Latest Revision: 20131121
    • Publication Date:
      20240829
    • Accession Number:
      10.1021/bi0519957
    • Accession Number:
      16475793