Engagement of Gab1 and Gab2 in erythropoietin signaling.
Several signaling cascades are activated during engagement of the erythropoietin receptor to mediate the biological effects of erythropoietin. The members of the insulin receptor substrate (IRS) family of proteins play a central role in signaling for various growth factor receptors and cytokines by acting as docking proteins for the SH2 domains of signaling elements, linking cytokine receptors to diverse downstream pathways. In the present study we provide evidence that the recently cloned IRS-related proteins, Gab1 and Gab2, of the Gab family of proteins, are rapidly phosphorylated on tyrosine during erythropoietin treatment of erythropoietin-responsive cells and provide docking sites for the engagement of the SHP2 phosphatase and the p85 subunit of the phosphatidylinositol 3'-kinase. Furthermore, our data show that Gab1 is the primary IRS-related protein activated by erythropoietin in primary erythroid progenitor cells. In studies to identify the erythropoietin receptor domains required for activation of Gab proteins, we found that tyrosines 425 and 367 in the cytoplasmic domain of the erythropoietin receptor are required for the phosphorylation of Gab2. Taken together, our data demonstrate that Gab proteins are engaged in erythropoietin signaling to mediate downstream activation of the SHP2 and phosphatidylinositol 3'-kinase pathways and possibly participate in the generation of the erythropoietin-induced mitogenic responses.
Wickrema
A
A
Section of Hematology-Oncology, University of Illinois at Chicago and West Side Veterans Affairs Medical Center, Chicago, Illinois 60607, USA. Awickrem@uic.edu
Uddin
S
S
Sharma
A
A
Chen
F
F
Alsayed
Y
Y
Ahmad
S
S
Sawyer
S T
ST
Krystal
G
G
Yi
T
T
Nishada
K
K
Hibi
M
M
Hirano
T
T
Platanias
L C
LC
D048868:Adaptor Proteins, Signal Transducing; D002460:Cell Line; D004921:Erythropoietin / Q000378:metabolism*; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D007700:Kinetics; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000032:analysis; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism; D017467:Receptors, Erythropoietin / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction
D048868:Adaptor Proteins, Signal Transducing; C098587:GAB1 protein, human; C490895:GAB2 protein, human; D047908:Intracellular Signaling Peptides and Proteins; D010750:Phosphoproteins; D017467:Receptors, Erythropoietin; D004921:Erythropoietin; D019000:Phosphotyrosine; D019869:Phosphatidylinositol 3-Kinases; C516724:PTPN11 protein, human; C509249:PTPN6 protein, human; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases