Protein kinase subcellular localization

SARA is a scaffolding protein that regulates the subcellular localization of inactivated R-Smads, potentially scaffolding the TGF-P receptor kinase to the Smad 2 substrate. Filamins are a family of actin polymerization proteins that also form scaffolds for a range of signaling proteins including SAP kinases such as MKK-4, small GTPases Rho and Ras, as well as Smad 2 and Smad 5. 

Fig. 1.36. Regulation of the sub-ceUular localization of the transcription factor SWI5 in yeast by phosphorylation. The subcellular localization of the SWI5 protein is regulated by phosphorylation/ dephosphorylation. In the phos-phorylated state, SWI5 is found in the cytoplasm, while in the under-phosphorylated state it is localized in the nucleus. Phosphorylation and dephosphorylation are catalyzed by either protein kinases or protein phosphatases and can be controlled via signal transduction chains.

The extent and specificity of the reactions of protein kinases and protein phosphatases are extremely dependent on the degree to which substrate and enzyme are localized at the same place in the cell. Many substrates of protein kinases occur either as membrane associated or particle associated forms (see 7.6.1, enzymes of glycogen metabolism). For protein kinases or protein phosphatases to perform their physiological function in a signal transduction process, they must be transported to the location of then-substrate in many cases (review Hubbard and Cohen, 1992 Mochly-Rosen, 1995). This is vahd both for the Ser/Tbr-specific protein kinases as well as for many Tyr-speci-fic protein kinases. In the course of activation of signal transduction pathways, com-partmentahzation of protein kinases, redistributed to new subcellular locations, is often observed. 

By bringing together various protein kinases and protein phosphatases, anchoring proteins organize signal transduction events and can create localized and efficient signal events at specific subcellular sites. 

Cytoplasmically localized protein tyrosine phosphatases have a catalytic domain and other structural elements that specify the subcellular localization and association with effector molecules. These structural elements contain sequence signals for nuclear localization, for membrane association and for association with the cytoskeleton (see Fig. 8.16). The presence of SH2 domains suggests that these molecules might interact with signaling pathways involving growth hormones and receptor tyrosine kinases. 

Discrete subcellular localization and protein interaction are other mechanisms by which this otherwise multifunctional protein kinase could achieve some degree... 

The principle of targeted localization is shown in Fig. 7.20. In addition to the binding site for the corresponding protein kinase (or protein phosphatase), the regulatory subunit has a specific binding site for an anchor protein, found at a subcellular site in the region where protein phosphorylation should take place. Through the interaction of anchor protein and localization subunit, the catalytic subunit is fixed at the desired location and is able to preferentially convert substrate localized at the same location. 

Among the protein kinases already discussed, there are some for which the function is linked with specific subcellular localization to a high degree. The anchoring proteins for protein kinases discussed below have been well characterized. 

An increase in cAMP and activation of protein kinase A are accompanied, in many cases, by a change in the subcellular location of protein kinase A holoenzymes containing RII subunits (see Section 7.3). This targeted localization is mediated by the AKAPs, of which more than 20 different members are known (review Feliciello et al., 2001). The AKAPs immobilize the PKA isoforms at specific subcellular sites by binding the RII subunits (Fig. 7.21). Binding of cAMP to the regulatory subunit releases the catalytic subunit that can phosphorylate substrates in the near vicinity. The released catalytic subunit can also be transferred to other compartments of the cell. Parallel to the increase in cAMP, translocation of the catalytic subunit is observed in many cells from the Golgi apparatus to the nucleus via the cytosol, and is accompanied by stimulation of transcription. 

---