Neuropeptides are implicated as growth factors in a variety of fundamental processes including development, inflammation, tissue regeneration, and neoplastic transformation (1-3). In particular, bombesin and its mammalian counterpart gastrin-releasing peptide bind to a GPCR 1 (4, 5) that promotes G␣ q -mediated activation of ␤ isoforms of phospholipase C (6 -8) to produce 2 s messengers: Ins(1,4,5)P 3 that mobilizes Ca 2ϩ from internal stores and diacylglycerol that activates conventional (␣, ␤ 1 , ␤ 2 , and ␥) and novel (␦, ⑀, , and ) PKCs (9, 10). The bombesin/gastrin-releasing peptide GPCR also interacts with members of the G 12 family leading to Rho-dependent actin remodeling and tyrosine phosphorylation of focal adhesion proteins, including FAK (10 -17). Subsequently, bombesin induces striking activation of serine phosphorylation cascades (11)(12)(13)(14) and promotes increased expression of immediate early response genes, stimulation of DNA synthesis, and cell proliferation (15-19). The mechanism(s) linking the early signaling pathways to the subsequent stimulation of cell proliferation remains incompletely understood.PKD (also initially known as PKC) is a serine/threonine protein kinase with structural, enzymology, and regulatory properties different from the PKC family members (20, 21). PKD most distinct characteristics are the presence of a catalytic domain distantly related to Ca 2ϩ -regulated kinases, a pleckstrin homology (PH) region that regulates enzyme activity and a highly hydrophobic stretch of amino acids in its Nterminal region (22)(23)(24). This N-terminal region also contains a tandem repeat of cysteine-rich, zinc finger-like motifs, which confers high affinity for phorbol esters and plays a negative role in the regulation of catalytic kinase activity (25-28). The identification of PKD-2 and PKD-3, similar in overall structure, primary amino acid sequence, and enzymology properties to PKD/PKC (29 -32), supports the notion that PKD isoenzymes constitute a separate family of serine protein kinases.PKD can be activated in intact cells through multiple G protein pathways, including G q , G i , and G 12 (33-39), as well as by biologically active phorbol esters, growth factors and antigen-receptor engagement (36, 37, 39 -45). In all these cases, rapid PKD activation is mediated by PKC-dependent phosphorylation of Ser-744 and Ser-748 within the activation loop of the catalytic domain of PKD (33, 46 -48). PKD activation is associated with its translocation to the plasma membrane and subsequent transient accumulation in the nucleus (25,28,50,51). These findings revealed that PKD is activated by multiple growth-promoting factors (22, 52) suggesting that it functions in mitogenic signaling. Indeed, we reported that PKD overexpression markedly potentiates DNA synthesis induced by the GPCR agonists bombesin and vasopressin in Swiss 3T3 cells (53), a cell line that has been used extensively as a model system to elucidate signal transduction pathways in the mitogenic action of GPCR agonists (1,54,55). Thes...