The role of protein kinase C (PKC) in cell signalling has been known for almost two decades and since then a whole family of PKC-like enzymes has been identified. In 1994 a novel PKC-related enzyme, PKC-mu, otherwise known as PKD, was identified. This widely expressed cytosolic serine-threonine kinase can be recruited to the trans-Golgi network and is therefore considered a modulator of cell trafficking. This was followed in 1999 by the identification of PKCnu, and in 2001 by the identification of PKD2, the constitutive expression of which was largely restricted to the pancreas, heart, lung, smooth muscle, brain and rapidly proliferating tissues such as testis and colonic crypts. PKD, PKCnu and PKD2 are now accepted as a distinct PKC-related family of protein kinases, called the PKD family. Since its identification, PKD has been shown to play a role in growth factor signaling as well as in stress-induced signaling. It enhances expression of anti-apoptotic genes through the activation of NFkB and is activated upon treatment of cells with genotoxic chemotherapeutics. Moreover, PKD has emerged as an important regulator of plasma membrane enzymes and receptors, in some cases mediating cross-talk between different signaling systems. Consequently, PKD may be implicated in a number of clinical conditions. For example it may play a role in the response to infectious/inflammatory disease since PKD has been shown to be involved in the down-stream response to receptor:antigen binding in T and B cells, neutrophils and mast cells. In addition PKD mediates the mast cell response to a variety of cytokines. Likewise, PKD mediates the mitogenic response to a variety of biological mediators and molecules able to regulate this activity may therefore be of use for the treatment of cancer. This is further supported by the findings that PKD mediates the biological responses elicited by PKC activation in small cell lung cancer cells. PKD inhibitors could have the potential to inhibit certain mitogenic responses and to sensitize cells for apoptosis induced by genotoxic chemotherapeutics. Metabolic control may also involve PKD since its cellular location in skeletal muscle changes upon transition between the fasted and the fed state and furthermore it plays a role in pre-adipocyte differentiation. Finally, PKD has been implicated in the cardiovascular system. Expressed in the myocardium and vascular smooth muscle and activated by oxidative stress, PKD is activated by key cardiovascular mediators such as angiotensin II, endothelin and PDGF. Modulation of PKD thus has the potential to modulate immune cell regulation, tumor progression, metabolic disorders and cardiovascular disease. The recent identification of PKD family members with a relatively restricted expression pattern suggests that in addition to exerting wide ranging therapeutic activity, modulators of PKD isoenzymes may have acceptable side-effect/tolerability profiles.

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