WHRY Pilot Project Program Investigators
Our long-term goal is to develop a comprehensive view of how cells detect differences in their adhesive environment and translate this information into changes in cell shape or migration. We are particularly interested in how these processes break down in cancer and neurodegenerative diseases.We have identified the Abl and Arg tyrosine kinases as essential regulators of cell migration and neuronal morphogenesis in response to adhesive cues and have demonstrated that Arg promotes lamellipodial protrusion, inhibits adhesion, and attenuates actomyosin contractility during integrin-mediated fibroblast migration on fibronectin. Using biochemical approaches and 4-D time-lapse imaging, we are studying how Abl and Arg help cells survey the adhesive landscape and coordinate the intracellular responses required for cell migration directed toward adhesive cues in normal and cancer cells. We are also interested in how the biochemical pathways we discovered promote the formation and
maintenance of neuronal networks in the developing vertebrate brain and how these mechanisms are compromised in psychiatric and neurodegenerative diseases.
Extensive Research Description
Adhesion receptors in cell migration, cancer metastasis, and neurodegeneration
Our long-term goal is to develop a comprehensive view of how cells detect differences in their adhesive environment and translate this information into changes in cell shape or migration. We are particularly interested in how these processes break down in cancer and neurodegenerative diseases.
Regulation of migration by adhesive cues in normal and cancer cells
Cells migrate by protruding a lamellipodium, anchoring this lamellipodium to the substrate via focal adhesion formation, contracting the cell body to move it forward, and detaching the trailing edge. Regulation of cell migration by adhesive cues is particularly important for organismal development and in tissue maintenance and repair. Our work over the past several years has identified the Abl and Arg tyrosine kinases as essential regulators of cell migration in response to adhesive cues. Importantly, we have demonstrated that Arg promotes lamellipodial protrusion, inhibits adhesion, and attenuates actomyosin contractility during integrin-mediated fibroblast migration on fibronectin. Using biochemical approaches and 4-D time-lapse imaging, we are studying how Abl and Arg help cells survey the adhesive landscape and coordinate the intracellular responses required for cell migration directed toward adhesive cues.
The normal control of cell migration is altered in cancer cells. During cancer metastasis, a tumor cell must dissolve adhesions and filamentous- (F-) actin networks and form new adhesions and F-actin networks to migrate and invade tissue. We recently identified the actin-regulatory protein cortactin as a substrate of Abl and Arg. Cortactin triggers F-actin-dependent dorsal waves in fibroblasts following PDGF treatment, resulting in adhesion dissolution, actin reorganization, and lamellipodial protrusion. We have shown that Abl/Arg-mediated phosphorylation of cortactin is required for this PDGF-induced dorsal wave response. Cortactin overexpression stimulates cell motility and its upregulation in several cancers, including breast cancer, correlates with poor prognosis. Our most recent studies suggest that Abl- and Arg- signaling is hyperactivated in highly invasive breast cancer cells. We are examining how cortactin promotes cell migration and how this process becomes activated in invasive breast cancer cells.
Neuronal Morphogenesis and Degeneration
The100 billion neurons of the human brain are wired together using fine extensions of the neurons called axons and dendrites. In order to form proper connections, growing axons and dendrites must recognize specific environmental cues and respond by rearranging the structure of their cytoskeleton.
Activation of the RhoA (Rho) GTPase in developing neurons by extracellular cues stimulates actomyosin contractility. Rho activation induces neurite retraction, a process require for pruning and refining neuronal connections. Inappropriate Rho activation in mature neurons leads to dendritic spine loss and dendritic regression. We find that Arg acts downstream of integrin adhesion receptors to activate the Rho inhibitor p190RhoGAP, thereby inhibiting Rho in response to adhesive cues. We have recently shown that the loss of Arg signaling through p190RhoGAP in Arg knockout mice compromises dendritic spine shape. These synapses fail, leading to a regression of cortical and hippocampal dendrite arbors and memory loss.
Alzheimer's Disease (AD) brains exhibit significant regression of hippocampal and cortical dendritic arbors. Importantly, dendritic arbor loss correlates with memory impairment in AD patients, which appears well before significant neuron death is observed. These phenotypes mirror those observed in Arg-deficient mice. We are examining whether Rho signaling pathways are dysregulated in mouse models of AD and attempting to arrest dendritic regression in these mice using specific inhibitors of Rho signaling pathway components.
- Warren, M.S., Gourley, S.L., Lin, Y.-C., Simpson, M.A., Taylor, J.R., Greer, C.A. and Koleske, A.J. (2012) Integrin ß1 signals through Arg to regulate postnatal dendritic arborization, synapse density, and behavior. J Neurosci. In press.
- Gourley, S.L., Olevska, A., Warren, M.S., Taylor, J., and Koleske, A.J. (2012) Arg kinase regulates prefrontal dendritic spine refinement and cocaine-induced plasticity. J Neurosci. In press.
- MacGrath, S.M. and Koleske, A.J. (2012) Cell Science at a glance: cortactin. J Cell Sci, In press.
- Mader, C.C., Oser, M., Magalhaes, M., *Condeelis, J., *Koleske, A.J., and Gil-Henn, H. (2011) EGF signaling through a Src-Arg-cortactin relay regulates breast cancer invasiveness by controlling invadopodia maturation and function. Cancer Research, 71(5):1
- Lin, Y.-C., and Koleske, A.J. (2010) Mechanisms that promote long-term synapse and dendrite stability: disruption in psychiatric and neurodegenerative disorders. Ann Rev Neurosci., 33:349-78.
- Gourley, S.L. Koleske, A.J., and Taylor, J.R. (2009) Loss of dendrite stabilization by the Abl-related gene (Arg) kinase regulates behavioral flexibility and sensitivity to cocaine. Proc. Natl. Acad. Sci. USA, 106(39):16859-64
- Bradley, W.D., and Koleske, A.J. Regulation of cell migration and morphogenesis by Abl family kinases: emerging mechanisms and physiological contexts. (2009) J. Cell Sci, in press.
- Lapetina, S., Mader, C.C., Machida, K., Mayer, B.J., and Koleske, A.J. (2009) Arg interacts with cortactin to promote adhesion-dependent cell edge protrusion. J. Cell Biol., 185: 503-19