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Mechanism of Tyrosine Kinase Signaling

Mechanism of tyrosine kinase signaling

Molecules with SH2 domain(s) [Machida K et al 2003 Molecular & Cellular Proteomics].

Receptors linked to tyrosine kinases control a host of important biological activities, including proliferation, differentiation, survival, adhesion and motility. Disregulated signaling by tyrosine kinases underlies a number of important human diseases, particularly cancer. Research efforts over the last several decades have elucidated the broad outline of tyrosine kinase signaling mechanism: Ligand binding to the receptors leads to activation of the tyrosine kinases resulting in increased tyrosine phosphorylation of the receptor or associated proteins. Phosphorylated sites then serve to recruit cytosolic effector proteins containing modular phosphotyrosine (pTyr) binding modules, such as the Src Homology 2 (SH2) domain.

Human genome encodes around 100 of these SH2 containing proteins. With so many molecules that can potentially respond to an upstream phosphorylation signal, one has to wonder what controls the temporal dynamics of the such a complex signaling network. Who gets to respond first and who responds later? In collaboration with Prof. Bruce Mayer's lab, we are developing new experimental strategies to probe how these molecules are recruited and how they interact with other proteins at the cell membrane.

Postsynaptic Actin Network

Actin cytoskeleton plays a central role in regulating the synapses of neuron cells. In the CNS (central nervous system), almost all of the excitatory synapses are formed on small dendritic protrusions called dendritic spines, which are rich in F-actin. The morphology of a dendritic spine, presumably controlled by the actin cytoskeleton, is known to be correlated with the efficacy of the synaptic transmissions. Conversely, remodeling of actin cytoskeleton is necessary for many forms of synaptic plasticity. Furthermore, the morphology of the spines is dynamic in vivo: the shape and the size of a spine continue to change over time even in adult brains. This type of morphological plasticity is believed to be important for storing new experiences and knowledge. Finally, abnormal spine morphologies were found to be linked to various cognitive disorders such as mental retardation, fragile X syndrome and autism. Therefore, we are interested in understanding the link between actin cytoskeleton and the synaptic functions. Two basic questions are: (a) how do cells remodel actin in order to produce the specific cytoskeletal organization; and (b) why remodeling of actin is needed for synaptic plasticity.

Postsynaptic actin network