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.
Selected Cancer-Related Publications:
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.
Cao X, Tanis KQ, Koleske AJ, Colicelli J. Enhancement of ABL kinase catalytic efficiency by a direct binding regulator is independent of other regulatory mechanisms. J Biol Chem. 2008 Nov 14;283(46):31401-7. Epub 2008 Sep 16
Hu H, Milstein M, Bliss JM, Thai M, Malhotra G, Huynh LC, Colicelli J. Integration of transforming growth factor beta and RAS signaling silences a RAB5 guanine nucleotide exchange factor and enhances growth factor-directed cell migration. Mol Cell Biol. 2008 Mar;28(5):1573-83. Epub 2007 Dec 26
Milstein M, Mooser CK, Hu H, Fejzo M, Slamon D, Goodglick L, Dry S, Colicelli J. RIN1 is a breast tumor suppressor gene. Cancer Res. 2007 Dec 15;67(24):11510-6.