PROTEIN KINASE D1: STRUCTURE, ACTIVATION, REGULATION, SUBSTRATES, AND FUNCTIONS. ROLE IN SKIN PATHOLOGY.
Keywords:
PKD1, Protein kinase D1, PRKD1, PKD2, PKD3, Inflammatory skin diseases, Skin cancer, HNC, Head and neck cancer, PKD1 reviewAbstract
Protein kinase D1 (PKD1) posses proproliferative and antidifferentiative functions in human and mouse keratinocytes, prodifferentive function in hTert (N/Tert-1 or N-hTERT) keratinocytes, participate also in wound-healing process in mouse epidermis. Loss of PKD2 enhanced keratinocytes-proliferative potential, while loss of PKD3 resulted in a progressive proliferation defect, loss of clonogenicity, and diminished tissue regenerative ability. This proliferation defect was correlated with upregulation of CDK4/6 inhibitor p15INK4B and induction of a p53-independent G1 cell-cycle arrest. Simultaneous silencing of PKD isoforms resulted in a more pronounced proliferation defect consistent with a predominant role for PKD3 in proliferating keratinocytes. There are no data concerning regulation of the PKD1, 2 and/or 3 kinase expression in skin. The mechanisms regulating PKD1 expression are merely studied only in pancreatic and prostate cancer cells. In skin pathology, the kinase is with increased expression in psoriatic lesions and basocellular carcinoma (BCC) and downregulated in head and neck spinocellular carcinoma (HNSCC). In the multistage mouse skin carcinogenesis model, the expression of PKD1 and CD34+ (cutaneous cancer stem-cell marker) are increased with increased expression of p53, p21, cMyc, cyclin B, p-CDK1, and Cdc25A and inhibited activation of extracellular signal-regulated kinase 1/2 (ERK1/2), increased nuclear factor-kappaB (NF-κB), cyclic adenosine 3′,5′-monophosphate-responsive elementbinding protein (CREB), and CCAATenhancer-binding protein (C/EBPs) activation by increased phosphorylation of c-Jun-N-terminal kinase 1/2 (JNK1/2), p38 and phosphatidylinositol 3-kinase (PI3K)/Akt and by increased downstream target gene expression, including inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX2), ornithine decarboxylase (ODC), and vascular endothelial growth factor (VEGF). The hyperplastic and inflammatory responses in PKD1-deficient mice to topical phorbol ester were significantly suppressed suggesting involvement of PKD1 in tumor promotion (and inflammation). Consistently, when subjected to two-stage chemical skin carcinogenesis protocol, these mice were resistant to papilloma formation when compared to control littermates. There are no other data for PKD1 participation in inflammatory skin process and expression in other premalignant skin diseases. Recently, hotspot-activating mutation in PKD1, resulting in an p.Glu710Asp aminoacid substitution, was detected in 73% of salivary Polymorphous low-grade adenocarcinoma (PLGA), associated with metastasis-free survival. Its increased expression is connected with late phases of malignant melanoma, associated with high metastatic potential. PKD1 participates in the pathology of inflammatory skin diseases and skin oncogenesis, but the mechanisms of regulation of its expression and action in skin in norm and in pathological processes are still unsufficient. PKD1 is upregulated merely in BCCs and in pancreatic cancer and downregulated in HNSCC, prostate, breast gastric, and colon cancers.
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