Interaction of the tyrosine phosphatase SHP-2 with Gab2 regulates Rho-dependent activation of the c-fos serum response element by interleukin-2.
Gab2 (Grb2-associated binder-2), a member of the IRS (insulin receptor substrate)/Gab family of adapter proteins, undergoes tyrosine phosphorylation in response to cytokine or growth factor stimulation and serves as a docking platform for many signal transduction effectors, including the tyrosine phosphatase SHP-2 [SH2 (Src homology 2)-domain-containing tyrosine phosphatase]. Here, we report that, following IL-2 (interleukin-2) stimulation of human T lymphocytes, SHP-2 binds tyrosine residues 614 and 643 of human Gab2 through its N- and C-terminal SH2 domains respectively. However, the sole mutation of Tyr-614 into phenylalanine is sufficient to prevent Gab2 from recruiting SHP-2. Expression of the Gab2 Tyr-614-->Phe (Y614F) mutant, defective in SHP-2 association, prevents ERK (extracellular-signal-regulated kinase) activation and expression of a luciferase reporter plasmid driven by the c-fos SRE (serum response element), indicating that interaction of SHP-2 with Gab2 is required for ERK activation in response to IL-2. Further investigation of IL-2-dependent induction of SRE showed that expression of a constitutively active mutant of the RhoA GTPase synergizes with IL-2 for SRE-driven transcription, whereas a dominant-negative mutant reduces the IL-2 response. Thus, in response to IL-2, full induction of the SRE requires ERK-dependent as well as Rho-dependent signals that target the Ets-box and the CArG-box respectively. We also report that the synergy between Gab2/SHP-2 and RhoA for IL-2-dependent CArG-box-driven transcription depends upon MEK (mitogen-activated protein kinase/ERK kinase) activation, and is likely to involve regulation of the serum response factor co-activator MAL. Our studies thus provide new insights into the role of Gab2 and SHP-2 in IL-2 signal transduction.
Arnaud
Mary
M
Inserm U461, Faculté de Pharmacie Paris-XI, 5 rue Jean-Baptiste Clément, 92290 Chatenay-Malabry, France.
Mzali
Rym
R
Gesbert
Franck
F
Crouin
Catherine
C
Guenzi
Christine
C
Vermot-Desroches
Claudine
C
Wijdenes
John
J
Courtois
Geneviève
G
Bernard
Olivier
O
Bertoglio
Jacques
J
D000209:Acute-Phase Proteins / Q000502:physiology*; D048868:Adaptor Proteins, Signal Transducing; D023081:CCAAT-Binding Factor / Q000502:physiology; D045744:Cell Line, Tumor; D005786:Gene Expression Regulation / Q000502:physiology; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology; D016762:Genes, fos / Q000502:physiology*; D005982:Glutathione Transferase; D006801:Humans; D007376:Interleukin-2 / Q000502:physiology*; D047908:Intracellular Signaling Peptides and Proteins; D015461:Leukemia, Prolymphocytic, T-Cell / Q000473:pathology; D020929:Mitogen-Activated Protein Kinase Kinases / Q000502:physiology; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology; D010455:Peptides / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism* / Q000502:physiology; D054593:SH2 Domain-Containing Protein Tyrosine Phosphatases; D027602:Serum Response Element / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D013601:T-Lymphocytes / Q000201:enzymology / Q000502:physiology; D014443:Tyrosine / Q000378:metabolism / Q000502:physiology; D018909:src Homology Domains / Q000502:physiology
D000209:Acute-Phase Proteins; D048868:Adaptor Proteins, Signal Transducing; D023081:CCAAT-Binding Factor; C490895:GAB2 protein, human; D007376:Interleukin-2; D047908:Intracellular Signaling Peptides and Proteins; D010455:Peptides; D010750:Phosphoproteins; C010781:acute-phase protein rho; D014443:Tyrosine; D005982:Glutathione Transferase; D020928:Mitogen-Activated Protein Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; C516724:PTPN11 protein, human; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D017027:Protein Tyrosine Phosphatases; D054593:SH2 Domain-Containing Protein Tyrosine Phosphatases