Tyrosine phosphorylation of the integrin beta 3 subunit regulates beta 3 cleavage by calpain.
Outside-in signaling of beta(3) integrins induces and requires phosphorylation at tyrosine 747 (Tyr(747)) and tyrosine 759 (Tyr(759)) of the beta(3) subunit, but the mechanism for this requirement is unclear. On the other hand, a key consequence of integrin signaling, cell spreading, is inhibited by calpain cleavage of beta(3) cytoplasmic domain. Here we show that beta(3) tyrosine phosphorylation inhibits calpain cleavage. Mutating both tyrosines to phenylalanine sensitizes beta(3) to calpain cleavage. Furthermore, phosphorylation at Tyr(747) and Tyr(759) of beta(3) in the focal adhesion sites and the leading edge of spreading platelets was differentially regulated. Selective dephosphorylation of Tyr(759) is associated with calpain cleavage at Tyr(759). Thus, one mechanism by which tyrosine phosphorylation promotes integrin signaling and cell spreading is its inhibition of calpain cleavage of the beta(3) cytoplasmic domain.
Xi
Xiaodong
X
Department of Pharmacology, University of Illinois, Chicago, Illinois 60612, USA.
Flevaris
Panagiotis
P
Stojanovic
Aleksandra
A
Chishti
Athar
A
Phillips
David R
DR
Lam
Stephen C T
SC
Du
Xiaoping
X
D000595:Amino Acid Sequence; D000818:Animals; D002154:Calpain / Q000502:physiology*; D002465:Cell Movement / Q000235:genetics; D002478:Cells, Cultured; D006801:Humans; D039661:Integrin beta3 / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D051379:Mice; D008817:Mice, Mutant Strains; D008969:Molecular Sequence Data; D010766:Phosphorylation; D015398:Signal Transduction / Q000235:genetics; D014443:Tyrosine / Q000235:genetics / Q000378:metabolism*
D039661:Integrin beta3; D014443:Tyrosine; D002154:Calpain