Protein Kinase A in cellular migration-Niche signaling of a ubiquitous kinase

Abstract

Cell migration requires establishment and maintenance of directional polarity, which in turn requires spatial heterogeneity in the regulation of protrusion, retraction, and adhesion. Thus, the signaling proteins that regulate these various structural processes must also be distinctly regulated in subcellular space. Protein Kinase A (PKA) is a ubiquitous serine/threonine kinase involved in innumerable cellular processes. In the context of cell migration, it has a paradoxical role in that global inhibition or activation of PKA inhibits migration. It follows, then, that the subcellular regulation of PKA is key to bringing its proper permissive and restrictive functions to the correct parts of the cell. Proper subcellular regulation of PKA controls not only when and where it is active but also specifies the targets for that activity, allowing the cell to use a single, promiscuous kinase to exert distinct functions within different subcellular niches to facilitate cell movement. In this way, understanding PKA signaling in migration is a study in context and in the elegant coordination of distinct functions of a single protein in a complex cellular process.

Keywords: Rho GTPases; cell migration; compartmentalization; ion channels; leading edge; protein kinase A; subcellular signaling; tyrosine kinases.

FIGURE 1

Schematic of PKA activity localized to distinct subcellular regions and structures in a migrating cell. Arrow highlights overall front to back gradient of subplasmalemmal PKA activity in the leading edge while arrowhead highlights hotspots of PKA activity. Though leading edge PKA activity has been well characterized, there are very few studies characterizing PKA activity in focal adhesions and microdomains. Images serve as representation of the concentration of PKA activity in these structures.

FIGURE 2

Schematic of functional connections between PKA and its targets in a migrating cell. Relationships are simplified for visual clarity. See text and Table 1 for details regarding functional connections.