John Colicelli, PhD
Dr. John Colicelli studies how cells detect stimulatory signals, transmit this information to subcellular compartments and respond appropriately. Of particular interest are signal transduction mechanisms mediated by RAS, the most common mutation-activated gene in human tumors. A better understanding of RAS function in cell proliferation and tumorigenesis should facilitate the development of effective cancer therapeutics.
To this end, Colicelli studies the pathways regulated by RIN1, a downstream effector. The RIN1 protein stimulates ABL tyrosine kinases, which can be oncogenic in hematopoietic tumors. Ongoing projects in this area include studies of how RIN1 promotes leukemogenesis, and whether this connection can be exploited in the development of novel therapeutics. In epithelial cell-derived tumors, RIN1 may play a very different role. Preliminary data suggest that RIN1 may function as a tumor suppressor in breast cancer. Researchers are continuing to examine this connection and its implications for diagnosis, prognosis and treatment of breast cancer.
Pancreatic ductal cancers, which almost universally carry activating mutations in the KRAS gene, are a more recent area of focus. Colicelli and his colleagues are part of a multi-lab effort to define signal transduction changes in pancreatic cancer and identify targets for therapeutic intervention.
Finally, a portion of the lab is studying the role of RIN1 in neuronal plasticity. RAS (upstream of RIN1) and ABL (downstream of RIN1) are known regulators of learning and memory. Their experiments with a Rin1-/- disruption mouse strain confirm a role for this pathway in learning, but the mechanism remains unclear.
Ting PY, Johnson CW, Fang C, Cao X, Graeber TG, Mattos C, Colicelli J. Tyrosine phosphorylation of RAS by ABL allosterically enhances effector binding. FASEB J. 2015 Sep;29(9):3750-61. doi: 10.1096/fj.15-271510. Epub 2015 May 21.
Balaji K, Mooser C, Janson CM, Bliss JM, Hojjat H, Colicelli J. RIN1 orchestrates the activation of RAB5 GTPases and ABL tyrosine kinases to determine the fate of EGFR. J Cell Sci. 2012 Dec 1;125(Pt 23):5887-96. doi: 10.1242/jcs.113688. Epub 2012 Sep 12.
Thai M, Ting PY, McLaughlin J, Cheng D, Muschen M, Witte ON, Colicelli J. ABL fusion oncogene transformation and inhibitor sensitivity are mediated by the cellular regulator RIN1. Leukemia. 2011 Feb;25(2):290-300. Epub 2010 Nov 19
Colicelli J. ABL tyrosine kinases: evolution of function, regulation, and specificity. Sci Signal. 2010 Sep 14;3(139):re6.
Colicelli J. Human RAS superfamily proteins and related GTPases. Sci STKE. 2004 Sep 7;2004(250):RE13.