Protein-tyrosine phosphatase-alpha and Src functionally link focal adhesions to the endoplasmic reticulum to mediate interleukin-1-induced Ca2+ signaling.
Calcium (Ca2+) signaling by the pro-inflammatory cytokine interleukin-1 (IL-1) is dependent on focal adhesions, which contain diverse structural and signaling proteins including protein phosphatases. We examined here the role of protein-tyrosine phosphatase (PTP) alpha in regulating IL-1-induced Ca2+ signaling in fibroblasts. IL-1 promoted recruitment of PTPalpha to focal adhesions and endoplasmic reticulum (ER) fractions, as well as tyrosine phosphorylation of the ER Ca2+ release channel IP3R. In response to IL-1, catalytically active PTPalpha was required for Ca2+ release from the ER, Src-dependent phosphorylation of IP3R1 and accumulation of IP3R1 in focal adhesions. In pulldown assays and immunoprecipitations PTPalpha was required for the association of PTPalpha with IP3R1 and c-Src, and this association was increased by IL-1. Collectively, these data indicate that PTPalpha acts as an adaptor to mediate functional links between focal adhesions and the ER that enable IL-1-induced Ca2+ signaling.
Wang
Qin
Q
Canadian Institutes of Health Research Group in Matrix Dynamics, Faculty of Dentistry, University of Toronto, Toronto, Ontario M5S 3E2, Canada.
Rajshankar
Dhaarmini
D
Branch
Donald R
DR
Siminovitch
Katherine A
KA
Herrera Abreu
Maria Teresa
MT
Downey
Gregory P
GP
McCulloch
Christopher A
CA
D000818:Animals; D020013:Calcium Signaling / Q000187:drug effects*; D002478:Cells, Cultured; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000201:enzymology*; D022001:Focal Adhesions / Q000187:drug effects / Q000201:enzymology*; D006801:Humans; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000378:metabolism; D007375:Interleukin-1 / Q000494:pharmacology*; D051379:Mice; D019000:Phosphotyrosine / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D054630:Receptor-Like Protein Tyrosine Phosphatases, Class 4 / Q000378:metabolism*; D019061:src-Family Kinases / Q000378:metabolism*
D053496:Inositol 1,4,5-Trisphosphate Receptors; D007375:Interleukin-1; D019000:Phosphotyrosine; D019061:src-Family Kinases; D054630:Receptor-Like Protein Tyrosine Phosphatases, Class 4