Bulinski, and G. such as wound healing, whereas its deregulation is a key factor contributing to tumor invasion and metastasis. Cell migration is often initiated by extracellular growth factors that activate receptor tyrosine kinase-dependent signaling, leading to extensive actin remodeling and the formation of unique structures termed membrane ruffles (18). These hallmark structures are important for cell motility and for invasive migration of cells through the extracellular matrix (51). Elucidating the molecular network that regulates and connects actin remodeling to cell migration is therefore fundamentally important. Rac1, a member of the Rho family small GTPases, plays a critical role in actin remodeling and motility (5). In response to growth factor Mouse monoclonal to NPT stimulation, Rac1 activates WAVE and the Arp2/3 multiprotein complex, which induces branching of actin filaments, resulting in membrane ruffling at the leading edge (lamellipodia or peripheral ruffles) and at the dorsal surface (dorsal ruffles). The induction of membrane ruffles is uniquely accompanied by Propacetamol hydrochloride a specialized form of endocytosis, fluid phase endocytosis, also termed macropinocytosis (14, 40). Distinct from other forms of endocytosis, macropinocytosis is initiated when extended membrane ruffles fuse with the plasma membrane, which generates large endocytic vesicles ( 0.1 Propacetamol hydrochloride m) termed macropinosomes (10, 52). Macropinocytosis provides an efficient route for taking up extracellular macromolecules and nutrients. As is the case for cell migration, macropinocytosis in most cell types is stimulated by growth factors (10, 52). In fact, macropinocytosis and directed cell movement are often correlated. For example, oncogenic Ras, Src, and phosphoinositide 3-kinase (PI3K) promote both macropinocytosis and motility (1, 24, 49, 53, 55). A constitutively active p21-activated kinase 1 (PAK1), a key effector for Rac1, stimulates actin membrane ruffle formation and macropinocytosis, with a concomitant increase in directed cell migration (14). Analysis of fibroblasts derived from WAVE2 knockout (KO) mice demonstrates deficiency in ruffle formation, macropinocytosis, and motility (51). Together, these observations reveal that macropinocytosis and cell motility are functionally connected and are subjected to the control of growth factor and oncogenic signaling. However, unlike the well-studied clathrin-dependent or caveola-mediated endocytosis, the regulation of macropinocytosis is still poorly understood. We have previously shown that HDAC6, a cytoplasmic member of the histone deacetylase family, promotes growth factor-induced cell motility (22). This unexpected finding is in stark contrast to the well-established function of the histone deacetylase family in histone acetylation-dependent chromatin remodeling and gene transcription (12). Overexpression of HDAC6 in fibroblasts results in two prominent phenotypes: global microtubule deacetylation and an increase in cell motility (22). Indeed, HDAC6 uniquely possesses a microtubule deacetylase activity (22, 31, 60). However, the mechanism by which HDAC6 regulates cell motility remains poorly understood. Although the microtubule network is a critical element in cell migration, whether microtubule deacetylation controlled by HDAC6 is the primary factor driving cell motility is not known. This has become an important issue, since -tubulin is not the exclusive substrate of HDAC6. Another prominent HDAC6 substrate recently identified is the molecular chaperone heat shock protein 90 (Hsp90). HDAC6-catalyzed deacetylation of Hsp90 is required for its full chaperone activity, which has been shown Propacetamol hydrochloride to regulate multiple signaling pathways (29, 33, 34). Identifying the relevant.