Molecular characterization of specific interactions between SHP-2 phosphatase and JAK tyrosine kinases.
Interactions between SHP-2 phosphotyrosine phosphatase and JAK tyrosine kinases have recently been implicated in cytokine signal transduction. However, the molecular basis of these interactions is not well understood. In this study, we demonstrate that SHP-2 is tyrosine-phosphorylated by and associated with JAK1 and JAK2 but not JAK3 in COS-1 cell cotransfection experiments. SHP-2 phosphatase activity appears not to be required for JAK and SHP-2 interactions because SHP-2 with a mutation at amino acid 463 from Cys to Ser, which renders SHP-2 inactive, can still bind JAKs. We further demonstrate that SHP-2 SH2 domains (amino acids 1-209) are not essential for the association of JAKs with SHP-2, and the region between amino acids 232 and 272 in SHP-2 is important for the interactions. Furthermore, tyrosine residues 304 and 327 in SHP-2 are phosphorylated by JAKs, and phosphorylated SHP-2 can associate with the downstream adapter protein Grb2. Finally, deletion of the N terminus but not the kinase-like domain of JAK2 abolishes the association of JAK2 with SHP-2. Taken together, these studies identified novel sequences for SHP-2 and JAK interactions that suggest unique signaling mechanisms mediated by these two molecules.
Yin
T
T
Walther Oncology Center, Indiana University School of Medicine, Indianapolis 46202, USA.
Shen
R
R
Feng
G S
GS
Yang
Y C
YC
D000818:Animals; D047908:Intracellular Signaling Peptides and Proteins; D053613:Janus Kinase 1; D053614:Janus Kinase 2; D053616:Janus Kinase 3; D051379:Mice; D010766:Phosphorylation; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases / Q000737:chemistry*; D011505:Protein-Tyrosine Kinases / Q000737:chemistry*; D011518:Proto-Oncogene Proteins; D017384:Sequence Deletion; D013329:Structure-Activity Relationship; D014443:Tyrosine / Q000378:metabolism
D047908:Intracellular Signaling Peptides and Proteins; D011518:Proto-Oncogene Proteins; D014443:Tyrosine; D011505:Protein-Tyrosine Kinases; C507905:Jak1 protein, mouse; C507926:Jak2 protein, mouse; C507935:Jak3 protein, mouse; D053613:Janus Kinase 1; D053614:Janus Kinase 2; D053616:Janus Kinase 3; 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