Protein kinase Cι: Human oncogene, prognostic marker and therapeutic target

Abstract

The Protein kinase C (PKC) family of serine/threonine kinases has been the subject of intensive study in the field of cancer since their initial discovery as major cellular receptors for the tumor promoting phorbol esters nearly thirty years ago. However, despite these efforts, the search for a direct genetic link between members of the PKC family and human cancer has yielded only circumstantial evidence that any PKC isozyme is a true cancer gene. This situation changed in the past year with the discovery that atypical protein kinase C iota (PKCι) is a bonafide human oncogene. PKCι is required for the transformed growth of human cancer cells and the PKCι gene is the target of tumor-specific gene amplification in multiple forms of human cancer. PKCι participates in multiple aspects of the transformed phenotype of human cancer cells including transformed growth, invasion and survival. Herein, we review pertinent aspects of atypical PKC structure, function and regulation that relate to the role of these enzymes in oncogenesis. We discuss the evidence that PKCι is a human oncogene, review mechanisms controlling PKCι expression in human cancers, and describe the molecular details of PKCι-mediated oncogenic signaling. We conclude with a discussion of how oncogenic PKCι signaling has been successfully targeted to identify a novel, mechanism-based therapeutic drug currently entering clinical trials for treatment of human lung cancer. Throughout, we identify key unanswered questions and exciting future avenues of investigation regarding this important oncogenic molecule.

Matrix metalloproteinase-10 is a critical effector of protein kinase Cι-Par6α-mediated lung cancer

“…Atypical PKCi is an oncogene that drives anchorageindependent growth through the Rho family GTPase Fields and Regala, 2007). Our data demonstrate that PKCi and PKCz play distinct roles in lung tumorigenesis; whereas PKCi is required for NSCLC transformation, PKCz is dispensible.…”

The RNA binding protein FXR1 is a new driver in the 3q26-29 amplicon and predicts poor prognosis in human cancers

“…In this report we provide mechanistic studies suggesting a novel role of FXR1 in the progression of NSCLC. FXR1 regulates ERK signaling pathway through interaction with PRKCI and ECT2, two known oncogenes within same 3q26-29 amplicon (7,23). PRKCI has been reported to be activated by PI3 Kinase, PDK1, RAS and SRC either alone or in association with the PAR complex, although the signaling mechanisms involved appear to differ in different tumor types (24).…”

Regulation of Protein Kinase C function by phosphorylation on conserved and non-conserved sites

“…These sites are not conserved on other PKC isoforms ( Figure 3). Since PKC has been implicated in many types of cancers and is the first PKC to be identified as a human oncogene [130], it will be intriguing to investigate the role of phosphorylation in PKC signalling and its effect on cell cycle deregulation/cancer progression. in the recruitment of PKC to the plasma membrane, and this is followed by phosphorylation at one or more sites such as the A-loop.…”