Research Abstract:
Signal transduction by growth factor receptors is a highly regulated process—activated receptors generate signals as they are internalized by endocytosis and degraded in the endosome-lysosome pathway. We have identified and studied the Rab GTPases and their exchange factors that orchestrate growth factor receptor trafficking. Recently, our lab has turned its attention to the investigation of a hominoid-specific gene that regulates growth factor receptor signaling. TBC1D3 belongs to a hominoid-specific gene family with no known orthologs outside the primate lineage. TBC1D3 is present on human chromosome 17 as 8 paralogs, all of which appear to be variably expressed in human tissues and in certain human tumors. Expression of TBC1D3 enhances cell proliferation in response to serum and growth factors. Molecular cell biology studies indicate that TBC1D3 enhances the activation of Ras by EGF and delays the endocytic trafficking of the internalized EGF receptor. Delayed trafficking of the EGFR appears to be due to suppressed ubiquitination of the activated EGFR, which leads to delayed lysosomal degradation. The cell and molecular biology of hominoid- and human-specific genes--a virtually untouched field of investigation--will significantly enlarge our understanding of human physiology. The human genome contains a relatively small number of genes that are hominoid- or human-specific and not present in mice or lower organisms. Human/hominoid-specific genes may modulate signaling or regulatory pathways that have evolved to a higher level of complexity and that distinguish humans from less complex species. These human-specific genes may operate at the transcriptional level, thereby influencing gene expression, or by regulating translation, altering protein deployment or turnover at the cellular level. They may impose control by regulating the assembly of macromolecular complexes that orchestrate cellular signaling events. The identification, expression and function of human-specific genes will advance our understanding of human biology and pathobiology into a uniquely new domain. |
Selected Publications:
Wainszelbaum MJ, Charron AJ, Kong C, Kirkpatrick DS, Srikanth P, Barbieri MA, Gygi SP, Stahl PD. The hominoid-specific oncogene TBC1D3 activates Ras and modulates EGF receptor signaling and trafficking. J Biol Chem 2008 283: 13233-13242.
Su X, Kong C, Stahl PD. GAPex-5 mediates ubiquitination, trafficking and degradation of epidermal growth factor receptor. J Biol Chem 2007 282(29): 21278-21284.
Magadan JG, Barbieri MA, Mesa R, Stahl PD, Mayorga LS. Rab22a regulates the sorting of transferring to recycling endosomes. Mol Cell Biol 2006 26: 2595-2614.
Hodzic D, Kong C, Wainzelbaum MJ, Charron AJ, Su X, Stahl PD. TBC1D3, a hominoid oncoprotein, is encloded by a cluster of paralogues located on chromosome 17q12. Genomics 2006 88: 731-736.
Kong C, Su X, Chen PI, Stahl PD. RIN1 interacts with signal transducing adaptor molecule (STAM) and mediates epidermal growth factor receptor trafficking and degradation. J Biol Chem 2007 282: 15294-15301. |