The Dual Roles of the Atypical Protein Kinase Cs in Cancer

Abstract

Atypical protein kinase C (aPKC) isozymes, PKCλ/ι and PKCζ, are now considered fundamental regulators of tumorigenesis. However, the specific separation of functions that determine their different roles in cancer is still being unraveled. Both aPKCs have pleiotropic context-dependent functions that can translate into tumor-promoter or -suppressive functions. Here, we review early and more recent literature to discuss how the different tumor types, and their microenvironments, might account for the selective signaling of each aPKC isotype. This is of clinical relevance because a better understanding of the roles of these kinases is essential for the design of new anti-cancer treatments.

Keywords: ECT2; Hedgehog; PD-L1; PHGDH; PKCζ; PKCλ/ι; SOX2; atypical PKCs; basal cell carcinoma; cancer; colorectal cancer; immunotherapy; kinase inhibitors; leukemia; lung cancer; metabolism; p62; polarity; prostate cancer; stroma; tumor promoter; tumor suppressor.

Figure 1.. The PKC Family

Classification of PKC isozymes by subfamily; classical, novel, and atypical with gene names, protein domains and their ligands.

Figure 2.. The Tumor Promoting Actions of PKCλ/ι

PKCλ/ι is activated downstream of the BCR-ABL oncogene and triggers a MEK-ERK-ETV5 signaling cascade that promotes SATB2-dependent inhibition of proliferation and B cell differentiation that contributes to the development of B-ALL. Additionally, PKCλ/ι is activated downstream of KRAS in LUAD and directs three signal transduction programs; (1) ECT2-RAC1-PAK-MEK1/2-ERK1/2 to promote cell survival; (2) rRNA biosynthesis through ECT2; (3) NOTCH3 transcriptional activation that contributes to stemness. Also, PRKCI is commonly amplified (3q26 AMP) in LSCC together with SOX2 and ECT2 to drive a Hedgehog-dependent transcriptional program that promotes stemness. Finally, PKCλ/ι maintains Hedgehog activation through GLI1 phosphorylation in BCC.

Figure 3.. Transcriptomics and Genetics of the aPKCs in Cancer

(A) PRKCI and PRKCZ median expression across all tumor samples and paired normal tissues for 31 tumor types. Plots generated with GEPIA 2 (Tang et al., 2017). Tumor type nomenclature follows TCGA study abbreviations guidelines (https://gdc.cancer.gov). (B) PRKCI and PRKCZ alterations in cancer using a curated set of non-redundant samples containing 159 studies with 35,693 patients and 36,917 samples for mutation data, and 158* studies with 27,410 patients and 28,457 samples for copy number variation data (cBioportal) (Cerami et al., 2012; Gao et al., 2013). *NEPC 2016 was omitted from CNV studies because it is not corrected for ploidy. (C) Somatic mutation profile of PRKCI (cBioportal). (D) Top 10 cancer types sorted by mutation frequency of PRKCI (cBioportal). (E) Top 10 cancer types sorted by CNV frequency of PRKCI (cBioportal). (F) Somatic mutation profile of PRKCZ (cBioportal). (G) Top 10 cancer types sorted by mutation frequency of PRKCZ (cBioportal). (H) Top 10 cancer types sorted by CNV frequency of PRKCZ (cBioportal).

Figure 4.. Tumor Suppression by Polarity Control

PRKCI mutations in the dibasic motif R480C (formerly R471C; red circle) contribute to a loss of substrate specificity that leads to loss of polarity and EMT. Additionally, polarity complexlocalized aPKC limits the pro-EMT actions of SNAI1. Finally, oncogenes such as ERBB2 can disrupt the PKCλ/ι-PAR3 complex and contribute to EMT.

Figure 5.. PKCζ is a Versatile Tumor Suppressor

PKCζ inhibits PHGDH, MYC, YAP, and β-catenin by direct phosphorylation to limit EMT, stem cell function, cell growth, and proliferation. PKCζ regulates ADAR2 and NF-κB to limit EMT and inflammation, respectively.

Figure 6.. Tumor Suppression by PKCλ/ι

PKCλ/ι blocks NEPC differentiation, cell growth and proliferation through inhibition of mTORC1-dependent metabolic reprogramming by directly phosphorylating LAMTOR2. Also, PKCλ/ι promotes Paneth cell differentiation, prevents cell death and interferon response by modulating the levels of JNK, ERK, YAP, and directly phosphorylating EZH2.

Figure 7.. Targetable Vulnerabilities of aPKC-Deficient Tumors

TGFβ inhibition with Galunisertib combined with anti PD-L1 antibodies (Ab) exploits a vulnerability created in highly mesenchymal CRC, like those from the serrated origin, by alleviating the stromal activation and boosting the antitumor response. Also, inhibition of PHGDH and/or DNMT activity with azacytidine (aza) can exploit a vulnerability created in therapy-resistant PCa to block NEPC differentiation and tumorigenesis.