PKC Translocation Mechanisms

One salient feature of PKC is its ability to translocate from a cytosolic (soluble) compartment to a membrane-bound (particulate) compartment in response to coincident elevation of the classical second messengers Ca2+ and DAG (Nishizuka 1995; Bataini and Mochly-Rosen 2007). This property has been widely exploited as a surrogate of PKC activation in a variety of studies. However, defining precise and generally applicable mechanisms of PKC translocation has been elusive. Ca2+ and phosphatidylserine recruit conventional PKC isoforms rapidly (seconds) and reversibly enough to be consistent with a diffusion controlled process for PKC translocation over normal intracellular distances (< 50 mm). Novel PKC isoforms, which lack the Ca2+-mediated membrane targeting capability, may translocate over minutes or longer due to rate-limiting conformational changes in the PKC regulatory domain itself (Robia et al. 2001). Similarly, multi-step translocation processes have been suggested for novel PKC isoforms based upon an antibody that recognizes a weakly membrane-bound, but inactive PKC conformation (Souroujon et al. 2004). Annexin V-microtubule interactions have also been shown to play a critical role in a slow multistep PKC-5 translocation process (Kheifets et al. 2006). Other types of translocation of PKC isoforms may depend upon trafficking of membranes through endosomal and Golgi compartments (Alvi et al. 2007). Alternatively, direct interactions of PKC isoforms with F-actin (Huang et al. 1997; Prekeris et al. 1996; Blobe et al. 1996) may reflect a form of directed one-dimensional diffusion as has been proposed for transcription factors moving along stretches of DNA (Elf et al. 2007). Thus, PKC may interact with membranes to restrict its influence to membrane proteins and by analogy with F-actin to limit its influence (under different circumstances) to the actin cytoskel-eton. Such an intriguing possibility for PKC/F-actin interactions must await thorough experimental verification. Nevertheless, it now seems unlikely given the diverse cellular functions regulated by PKC that it utilizes a single general mechanism to control subcellular localization or transport. Such versatility in regulatory strategies may simply be yet another manifestation of the evolutionary success of the PKC family.

Atypical PKCs are readily distinguished from conventional and novel PKCs by not undergoing translocation in response to phorbol esters or DAGs (Bataini and

Mochly-Rosen 2007; Suzuki et al. 2003; Moscat and Diaz-Meco 2000; Hirai and Chida 2003). However, the existence of nuclear localization and export signals in both aPKCZ and aPKC^ is consistent with evidence that they undergo dynamic nuclear-cytoplasmic shuttling (Perander et al. 2001). So, while extensive proteinprotein interaction networks appear to be a central feature of aPKC signaling, these PKC family members are also versatile and not restricted to functioning only in large stable macromolecular complexes.

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