Examples of Specific Isozyme Functions

An abundance of functions have been ascribed to the protein kinase C family in general, and to specific isozymes. Biochemical analyses have shown, for example, that protein kinase Ce regulates the actin-based cytoskeleton, with a defined actin-binding motif identified between the C1A and C1B domains of this isozyme. As another example, protein kinase CPII specifically phosphorylates the nuclear protein, lamin B, in human erythroleukemia cells, a phosphorylation that is required for proliferation of these cells.

The generation of knockout mice defective in specific protein kinase C isozymes is beginning to shed light on some of the physiological functions of protein kinase C. Disruption of the gene for protein kinase Cy results in mice that appear relatively normal, with only modest effects on learning and memory, indicating this isozyme either is not essential for viability or its function can be compensated by other isozymes.

However, one striking difference between knockout and wild-type mice has been characterized: mice lacking protein kinase Cy display reduced responses to nonnoxious pain stimuli following painful stimulation such as resulting from nerve injury, reduction in a phenomenon referred to as neuropathic pain. Studies with knockout mice in protein kinase Ce have also implicated this isozyme as a potential target for pain and, also, anxiety, for example, mice lacking this isozyme display less anxiety in response to threatening situations. Targeted disruption of the gene encoding protein kinase CP results in mice with an impaired immune response, with analysis of B cells from these mice revealing that the P isozymes are involved in B-cell activation. However, the molecular basis for many of the physiological differences observed in knockout mice is largely unresolved.

The protein kinase C isozymes do have some unifying regulatory roles. For example, a large number of both G protein-coupled receptors and tyrosine kinase receptors are desensitized to incoming information as a result of direct phosphorylation by protein kinase C. For example, members of the muscarinic receptor family, the P-adrenergic receptor, and the visual receptor, rhodopsin, are phosphorylated to reduce the coupling of these proteins to the relevant G protein. This type of desensitization complements that by G protein receptor kinases (GRKs), kinases that specifically phosphorylate the active conformation of the receptor. Typically, protein kinase Cs modify both liganded and nonliganded forms of the receptor, a modification that tends to be slower and has been proposed to be important for desensitizing cells to low levels of stimulation.

The uncontrolled activity of protein kinase C has long been implicated in tumorogenesis given the profound effects of phorbol esters in tumor promotion. Recently, high levels of expression of protein kinase CPII have been implicated in the first steps in colon cancer.

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