A role for SHPS-1/SIRPalpha1 in IL-1beta- and TNFalpha-dependent signaling.
We investigated the role of SHPS-1/SIRPalpha1 in IL-1beta- and TNFalpha-dependent signaling that leads to the activation of Erk 1/2 and Akt. Treatment of Balb3T3 cells with IL-1beta or TNFalpha activated tyrosine phosphorylation of SHPS-1, its association with SHP-2 and the phosphorylation of Erk 1/2 and Akt. PP1, a specific inhibitor for the Src family protein tyrosine kinases, strongly inhibited tyrosine phosphorylation of SHPS-1 and complex formation of SHPS-1 with SHP-2 by IL-1beta. In addition, PP1 substantially inhibited the IL-2beta- and TNFalpha-dependent activation of Erk 1/2 and Akt. Exogenous expression of either SHPS-1 mutants that lack SHP-2 binding function or a dominant negative mutant of SHP-2 markedly inhibited the activation of Erk 1/2 and Akt by IL-1beta, whereas wild type SHPS-1 did not. Moreover, IL-1beta-stimulation induced association of SHPS-1 with IL-1RAcP, a second subunit of IL-1 receptor, whereas expression of SHPS-1 mutant that lack SHP-2 binding function clearly blocked the association and tyrosine phosphorylation of endogenous SHPS-1. Taken together, our results strongly suggest that activation of Erk 1/2 and Akt by proinflammatory cytokines requires tyrosine phosphorylation of SHPS-1 and subsequent association of SHPS-1 with SHP-2.
Ruhul Amin
Ali Reja Mohammad
AR
Laboratory of Molecular Pathogenesis, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.
Machida
Kazuya
K
Oshima
Kumi
K
Oo
Myat Lin
ML
Thant
Aye Aye
AA
Senga
Takeshi
T
Matsuda
Satoru
S
Akhand
Anwarul Azim
AA
Maeda
Akito
A
Kurosaki
Tomohiro
T
Hamaguchi
Michinari
M
D016475:3T3 Cells; D000818:Animals; D000943:Antigens, Differentiation; D007375:Interleukin-1 / Q000502:physiology*; D008562:Membrane Glycoproteins / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D039842:Neural Cell Adhesion Molecule L1 / Q000378:metabolism / Q000502:physiology*; D010766:Phosphorylation; D011971:Receptors, Immunologic; D015398:Signal Transduction / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*; D014443:Tyrosine / Q000378:metabolism
D000943:Antigens, Differentiation; D007375:Interleukin-1; D008562:Membrane Glycoproteins; D039842:Neural Cell Adhesion Molecule L1; C501922:Sirpa protein, mouse; D011971:Receptors, Immunologic; D014409:Tumor Necrosis Factor-alpha; D014443:Tyrosine