Andrew D. Catling, PhD
Cell fate is determined by the complex interplay of signals from soluble factors and extracellular matrix components. Temporal integration of these signals is required for proliferation of many normal cells, and indeed loss of adhesion signaling results in rapid programmed cell death. Furthermore, the spatial integration of signals from adhesion receptors and soluble factors is a critical regulator of directional cell motility, for instance during ontogeny and immune cell function. Importantly, these mechanisms are frequently subverted in human disease, most notably during neoplastic transformation: hallmark characteristics of cancer cells are anchorage-independent growth and survival, and inappropriate motility that likely contributes to metastasis.
The ERK signaling pathway entrained by the Ras oncogene is a key regulator of proliferation, survival and motility. My laboratory is using biochemical, molecular, cell biological and mouse genetic techniques to elucidate mechanisms by which adhesion and growth factor signals are integrated to modify the temporal and spatial activation of ERK. The ultimate goal of this work is to understand how cancer cells circumvent normal safeguards ensuring anchorage-dependent signaling, and to identify molecular targets for therapeutic intervention.
One promising therapeutic avenue is to target isozyme-specific scaffolding molecules within the ERK pathway. Scaffolding molecules are thought to promote the assembly of specific combinations of signaling molecules and direct these complexes to appropriate downstream targets. In this way, the generic ERK pathway can be tailored to coordinately regulate multiple downstream targets in a scaffold-specific manner. Therapeutic intervention at the level of the scaffold might therefore enable one to selectively target specific pathological functions of the ERK pathway without affecting its many other “housekeeping” roles in normal cells. My laboratory is interested in the function of the putative scaffold MEK Partner 1, or MP1, and we are using mouse knock-out approaches in combination with molecular and biochemical experiments to investigate the biological function of this protein. Of particular interest is our finding that MP1 physically associates with two specific enzymes involved in adhesion signaling to ERK, suggesting that MP1 might function to integrate adhesion and growth factor signals in the ERK pathway.
Eblen, S. T., Slack, J. K., Weber, M. J., and Catling, A. D. (2002) Rac Signaling Can Potentiate ERK2 Activation by Facilitating the MEK/ERK Interaction. Mol. Cell. Biol., 22:6023-6033.
Catling, A. D., Eblen, S. T., Schaeffer, H. J., and Weber, M. J. (2001) Scaffold-protein regulation of the MAP kinase cascade. Methods in Enzymology, 332:368-387.
Nguyen, D. H. D., Catling, A. D., Webb, D. J., Sankovic, M., Walker, L. A., Somlyo, A., Weber, M. J., and Gonias S. L. (1999) Myosin light chain kinase regulates motility in an integrin-selective manner in urokinase-type plasminogen activator-treated MCF-7 cells. J. Cell Biol., 146:149-164.
Schaeffer, H. J., Catling, A. D., Eblen, S. T., Collier, L. S., Krauss, A., and Weber, M. J. (1998) MP1: a MEK binding partner that enhances enzymatic activation of the MAP kinase cascade. Science, 281:1668-1671.
Zecevic, M., Catling, A. D., Eblen, S. T., Renzi, L., Hittle. J. C., Yen, T. J., Gorbsky, G. J., and Weber, M. J. (1998) Active MAP kinase in mitosis: localization and association with the motor protein CENP-E. J. Cell Biol., 142:1547-1588.
Catling, A. D., Schaeffer, H-J., Reuter, C. W. M., Reddy, R., and Weber, M. J. (1995) A proline-rich sequence unique to MEK1 and MEK2 is required for Raf binding and regulates MEK function. Mol. Cell. Biol., 15:5214-5225.
Jelinek, T., Catling, A. D., Reuter, C. W. M., Moodie, S. A., Wolfman, A.,
and Weber, M. J. (1994) RAS and RAF form a signaling complex with MEK-1
but not MEK-2. Mol. Cell Biol., 14: 8212-8218.