Mouse models of altered protein kinase A signaling

Abstract

Protein kinase A (PKA) is an evolutionarily conserved protein which has been studied in model organisms from yeast to man. Although the cAMP-PKA signaling system was the first mammalian second messenger system to be characterized, many aspects of this pathway are still not well understood. Owing to findings over the past decade implicating PKA signaling in endocrine (and other) tumorigenesis, there has been renewed interest in understanding the role of this pathway in physiology, particularly as it pertains to the endocrine system. Because of the availability of genetic tools, mouse modeling has become the pre-eminent system for studying the physiological role of specific genes and gene families as a means to understanding their relationship to human diseases. In this review, we will summarize the current data regarding mouse models that have targeted the PKA signaling system. These data have led to a better understanding of both the complexity and the subtlety of PKA signaling, and point the way for future studies, which may help to modulate this pathway for therapeutic effect.

Differential Regulation of RasGAPs in Cancer

“…In this context, it should be noted that the localization of protein kinases such as PKC and PKA is regulated by scaffold proteins, including RACKs, A kinase anchoring proteins (AKAPs), and annexins, [79][80][81][82][83] all of which facilitate the complex and spatiotemporal targeting of PKC and PKA to unique subcellular localization to be part of specialized signaling complexes. The complex interplay of protein kinases with their specific scaffolds could therefore determine NF1 and, as outlined below, p120GAP activity and localization.…”

Lessons from Mouse Models of Thyroid Cancer

“…However, it is unclear as to the importance of the TSHR=cAMP=PKA pathway in thyroid cancer initiation. Gsa mutations are only found in a small percentage of thyroid cancer, and a minority of patients with McCune-Albright syndrome who have upregulation of cAMP production develop thyroid cancer (38).…”

Targeting cAMP/PKA pathway for glycemic control and type 2 diabetes therapy

“…1) (Smith et al 2006, Pidoux & Tasken 2010). Mice with global or conditional mutants of R subunits, C subunits, or AKAPs have been generated (Kirschner et al 2009) and greatly enhanced our understanding of the role of cAMP/PKA in different physiological and pathological processes, such as neural synaptic plasticity (Rosenmund et al 1994), cardiac hypertrophy (Antos et al 2001, Enns et al 2010, tumor progression (Kirschner et al 2000), and glucose homeostasis (Niswender et al 2005, Willis et al 2011). …”