Combinatorial ShcA Docking Interactions Support Diversity in Tissue Morphogenesis

Abstract

Changes in protein-protein interactions may allow polypeptides to perform unexpected regulatory functions. Mammalian ShcA docking proteins have amino-terminal phosphotyrosine (pTyr) binding (PTB) and carboxyl-terminal Src homology 2 (SH2) domains, which recognize specific pTyr sites on activated receptors, and a central region with two phosphorylated tyrosine-X-asparagine (pYXN) motifs (where X represents any amino acid) that each bind the growth factor receptor-bound protein 2 (Grb2) adaptor. Phylogenetic analysis indicates that ShcA may signal through both pYXN-dependent and -independent pathways. We show that, in mice, cardiomyocyte-expressed ShcA directs mid-gestational heart development by a PTB-dependent mechanism that does not require the pYXN motifs. In contrast, the pYXN motifs are required with PTB and SH2 domains in the same ShcA molecule for the formation of muscle spindles, skeletal muscle sensory organs that regulate motor behavior. Thus, combinatorial differences in ShcA docking interactions may yield multiple signaling mechanisms to support diversity in tissue morphogenesis.

The ShcA SH2 domain engages a 14-3-3/PI3′K signaling complex and promotes breast cancer cell survival

“…18 Despite this fact, we observe a modest increase in the latency of tumor onset in MT/ShcA þ /R397K (herein referred to as MT/ShcR397K) females relative to MT controls ( Figure 1a). We also demonstrate that mammary tumor outgrowth was significantly reduced in MT/ShcR397K mice, both at 4 and 6 weeks following first physical palpation of the primary tumor (Figure 1b).…”

“…18 Thus, SH2-mediated ShcA signaling is compromised both in the tumor epithelium and stromal cell types. To confirm that the ShcR397K mutant is acting in a cell autonomous fashion, we established cell lines from MT (#2186) and MT/ShcR397K (#9907) mammary tumors.…”

“…The ShcR397K allele is expressed under the control of the endogenous ShcA promoter, which allows us to examine the importance of SH2-driven ShcA signaling at physiologically relevant levels. 18 We were unable to generate ShcA…”

The adaptor protein Shc integrates growth factor and ECM signaling during postnatal angiogenesis

“…11 Interestingly, mice with a conditional deletion of Shc in specific organs such as skeletal muscle, 11 thymocytes, 14 or brain 12 live to adulthood, exhibiting defects only in the function of the tissue in which Shc was removed. Similarly, we now show that endothelial Shc expression is not required for embryonic development, but is required postnatally for angiogenesis.…”

“…More detailed gene-targeting work has shown that the expression of the PTB domain of Shc specifically in cardiomyocytes is critical for midgestational heart development and embryonic life. 11 Conditional knockout strategies have shown that Shc is also important for the proper development/function of other organs such as skeletal muscle, 11 brain, 12 cardiomyocytes, 13 and thymocytes, 14 because tissue-specific deletion of Shc resulted in living but underdeveloped mice. To address the role of Shc in angiogenesis in vivo, we studied loss of Shc function using morpholino (MO) antisense technology in zebrafish.…”