PSM/SH2-B distributes selected mitogenic receptor signals to distinct components in the PI3-kinase and MAP kinase signaling pathways.
The Pro-rich, PH, and SH2 domain containing mitogenic signaling adapter PSM/SH2-B has been implicated as a cellular partner of various mitogenic receptor tyrosine kinases and related signaling mechanisms. Here, we report in a direct comparison of three peptide hormones, that PSM participates in the assembly of distinct mitogenic signaling complexes in response to insulin or IGF-I when compared to PDGF in cultured normal fibroblasts. The complex formed in response to insulin or IGF-I involves the respective peptide hormone receptor and presumably the established components leading to MAP kinase activation. However, our data suggest an alternative link from the PDGF receptor via PSM directly to MEK1/2 and consequently also to p44/42 activation, possibly through a scaffold protein. At least two PSM domains participate, the SH2 domain anticipated to link PSM to the respective receptor and the Pro-rich region in an association with an unidentified downstream component resulting in direct MEK1/2 and p44/42 regulation. The PDGF receptor signaling complex formed in response to PDGF involves PI 3-kinase in addition to the same components and interactions as described for insulin or IGF-I. PSM associates with PI 3-kinase via p85 and in addition the PSM PH domain participates in the regulation of PI 3-kinase activity, presumably through membrane interaction. In contrast, the PSM Pro-rich region appears to participate only in the MAP kinase signal. Both pathways contribute to the mitogenic response as shown by cell proliferation, survival, and focus formation. PSM regulates p38 MAP kinase activity in a pathway unrelated to the mitogenic response.
Deng
Youping
Y
Department of Biological Sciences, The University of Southern Mississippi, Hattiesburg, MS 39406, USA.
Xu
Hu
H
Riedel
Heimo
H
D000818:Animals; D001483:Base Sequence; D049109:Cell Proliferation; D017931:DNA Primers; D004331:Drosophila melanogaster; D004791:Enzyme Inhibitors / Q000494:pharmacology; D020935:MAP Kinase Signaling System; D051379:Mice; D041681:NIH 3T3 Cells; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D011975:Receptors, Mitogen / Q000378:metabolism*; D015398:Signal Transduction; D018909:src Homology Domains
D017931:DNA Primers; D004791:Enzyme Inhibitors; D011975:Receptors, Mitogen; D019869:Phosphatidylinositol 3-Kinases