Gab2, a new pleckstrin homology domain-containing adapter protein, acts to uncouple signaling from ERK kinase to Elk-1.
We describe a novel human adapter molecule containing a pleckstrin homolgy (PH) domain at the N terminus that is closely related to human Grb2-associated binder 1, Gab1, and Drosophila daughter of sevenless. We designate this protein as Gab2. Northern blot analysis indicates that Gab2 is widely expressed and has an overlapping but distinctive expression pattern as compared with Gab1, with high levels of Gab2 mRNA detected in the heart, brain, placenta, spleen, ovary, peripheral blood leukocytes, and spinal cord. Upon tyrosine phosphorylation, Gab2 physically interacts with Shp2 tyrosine phosphatase and Grb2 adapter protein. Strikingly, Gab2 has an inhibitory effect on the activation of Elk-1-dependent transcription triggered by a dominant active Ras mutant (RasV12) or under growth factor stimulation, whereas Gab1 acts to potentiate slightly the Elk-1 activity in the same system. In contrast to the reciprocal effects of Gab1 and Gab2 in mediating Elk-1 induction, these two molecules have a similar function in extracellular signal-regulated kinase activation induced by either oncogenic Ras or growth factor stimulation. Taken together, these results argue that Gab1 and Gab2, two closely related PH-containing adapter proteins, might have distinct roles in coupling cytoplasmic-nuclear signal transduction. This is the first evidence that an intracellular molecule with a PH domain operates as a negative effector in signal relay to the regulation of gene expression.
Department of Biochemistry and Molecular Biology, and Walther Oncology Center, Indiana University School of Medicine, Indianapolis, Indiana 46202-5254, USA.
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D048868:Adaptor Proteins, Signal Transducing; D000595:Amino Acid Sequence; D001483:Base Sequence; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D002460:Cell Line; D003001:Cloning, Molecular; D004268:DNA-Binding Proteins; D004789:Enzyme Activation; D005786:Gene Expression Regulation; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008969:Molecular Sequence Data; D010750:Phosphoproteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D010766:Phosphorylation; D015221:Potassium Channels / Q000378:metabolism*; D011485:Protein Binding; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger / Q000378:metabolism; D016415:Sequence Alignment; D015398:Signal Transduction; D014157:Transcription Factors; D050807:ets-Domain Protein Elk-1; D018631:ras Proteins / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D004268:DNA-Binding Proteins; C494112:ELK1 protein, human; C490895:GAB2 protein, human; D047908:Intracellular Signaling Peptides and Proteins; D010750:Phosphoproteins; D015221:Potassium Channels; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D014157:Transcription Factors; D050807:ets-Domain Protein Elk-1; D017871:Calcium-Calmodulin-Dependent Protein 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; D018631:ras Proteins