Dok-R, also known as Dok-2/FRIP, belongs to the DOK family of signaling molecules that become tyrosinephosphorylated by several different receptor and cytoplasmic tyrosine kinases. Tyrosine phosphorylation of DOK proteins establishes high affinity binding sites for other signaling molecules leading to activation of a signaling cascade. Here we show that Dok-R associates with c-Abl directly via a constitutive SH3-mediated interaction and that this binding requires a PMMP motif in the proline-rich tail of Dok-R. The Dok-R-Abl interaction is further enhanced by an active c-Abl kinase, which requires the presence of its SH2 domain. Interaction of Dok-R with c-Abl also results in an increase in c-Abl tyrosine phosphorylation and kinase activity. Furthermore, we demonstrate that this increase in kinase activity correlates with a concomitant increase in c-Ablmediated biological activity as measured by the formation of actin microspikes. Our data are the first to demonstrate that Dok-R and c-Abl interact in both a constitutive and inducible fashion and that Dok-R influences the intracellular kinase and biological activity of c-Abl. Activation of receptor and cytoplasmic tyrosine kinases (TK)1 induces tyrosine phosphorylation of target proteins that initiates a series of protein-protein interactions (1). One of the many targets of TK-mediated signaling pathways is the actin cytoskeleton (2). Actin cytoskeletal rearrangements are important fundamental events that occur during a variety of cellular processes such as adhesion, spreading, migration, proliferation, and differentiation (2). Reorganization of the actin cytoskeleton involves cross-talk between a multitude of different signaling pathways involving kinases, integrins, and other adhesion molecules that target the actin cytoskeletal machinery. Many of these signaling proteins, including the integrin receptors and the cytosolic c-Abl tyrosine kinase, associate directly with the cytoskeleton.Tyrosine phosphorylation of docking and adapter proteins by receptor and cytosolic TKs promotes signal amplification by providing high affinity binding sites for numerous intracellular signaling molecules containing Src homology 2 (SH2) domains or phosphotyrosine binding (PTB) domains. Protein-protein interactions can also occur in a non-inducible manner as seen with the constitutive interaction between Src homology 3 (SH3) domains binding proline-rich motifs. Pleckstrin homology (PH) domains on signaling proteins recognize phospholipids and assist in recruitment of the protein to the plasma membrane. In addition to their role in mediating protein interactions, many of these modular domains found in cytoplasmic TKs also serve to regulate the host kinase.Similar to Src family kinases, c-Abl kinase activity is tightly regulated through intramolecular interactions involving its amino-terminal SH3 domain-containing region (3-5) and can be activated by epidermal and platelet derived growth factors in addition to Src and Src-like kinases (6). c-Abl contains a large array of functional d...
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