Molecular interactions of SHP1 and SHP2 in IL-3-signalling.
SHP1 and SHP2 tyrosine phosphatases have both been implicated in signalling pathways downstream of the interleukin-3 (IL-3) receptor. We have investigated the co-association of SHP1 and SHP2 with tyrosine-phosphorylated proteins in IL-3-dependent BaF/3 cells. We demonstrate that both SHP1 and SHP2 associate with Aic2A (beta chain of the IL-3 receptor), Gab2 and the paired inhibitory receptor B (PIR-B). The individual SH2 domains of SHP2 can independently bind Gab2, potentially important for the adapter function of SHP2. Association of both phosphatases with Aic2A and Gab2 increases upon IL-3 treatment. Recruitment of SHP1 to PIR-B also increases in response to IL-3, suggesting a functional link between inhibitory and cytokine receptor signalling. Aic2A is a rapid target for dephosphorylation following IL-3 stimulation and substrate-trapping versions of both phosphatases identify Aic2A and Gab2 as substrates for SHP1 and SHP2. These studies suggest that SH2-domain interactions are important for targetting these phosphatases to their substrates.
Wheadon
Helen
H
Department of Pharmacy and Pharmacology, University of Bath, Claverton Down, BA2 7AY, Bath, UK.
Paling
Nicholas R D
NR
Welham
Melanie J
MJ
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D002460:Cell Line; D007377:Interleukin-3 / Q000378:metabolism* / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins; D010750:Phosphoproteins / Q000378:metabolism; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism*; D011971:Receptors, Immunologic / Q000378:metabolism; D018123:Receptors, Interleukin / Q000378:metabolism; D016185:Receptors, Interleukin-3 / Q000378:metabolism*; D054593:SH2 Domain-Containing Protein Tyrosine Phosphatases; D015398:Signal Transduction / Q000502:physiology*; D013379:Substrate Specificity; D018909:src Homology Domains
D048868:Adaptor Proteins, Signal Transducing; C490894:Gab2 protein, mouse; D007377:Interleukin-3; D047908:Intracellular Signaling Peptides and Proteins; D010750:Phosphoproteins; C105949:Pirb protein, mouse; D011971:Receptors, Immunologic; D018123:Receptors, Interleukin; D016185:Receptors, Interleukin-3; C074452:interleukin 3 receptor-like molecule; C072185:Csf2rb2 protein, mouse; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases; C516725:Ptpn11 protein, mouse; C509248:Ptpn6 protein, mouse; D054593:SH2 Domain-Containing Protein Tyrosine Phosphatases