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Deciphering the Role of Protein Kinase D1 (PKD1) in Cellular Proliferation

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Deciphering the Role of Protein Kinase D1 (PKD1) in Cellular Proliferation Author Manuscript Published OnlineFirst on July 16, 2019; DOI: 10.1158/1541-7786.MCR-19-0125 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 1 Deciphering the role of protein kinase D1 (PKD1) in cellular proliferation 2 Ilige Youssefa,b and Jean-Marc Ricorta,b,c,* 3 4 aCentre National de la Recherche Scientifique, CNRS UMR_8113, Laboratoire de Biologie et 5 Pharmacologie Appliquée, F-94230 Cachan, France 6 bÉcole Normale Supérieure Paris-Saclay, Université Paris-Saclay, F-94230 Cachan, France 7 cCentre de Recherche des Cordeliers, INSERM, Sorbonne Université, USPC, Université Paris Descartes, 8 Université Paris Diderot, F-75006 Paris, France 9 10 Corresponding Author: Ricort Jean-Marc; email: [email protected]; address: Centre 11 de Recherche des Cordeliers, Laboratoire de Physiopathologie Orale Moléculaire, 15 rue de l’école de 12 médecine, 75006 Paris, France 13 14 Running Title: The role of PKD1 in cell proliferation 15 16 Disclosure of Potential Conflicts of Interest 17 No potential conflicts of interest were disclosed. 18 19 20 21 22 23 24 25 1 Downloaded from mcr.aacrjournals.org on October 1, 2021. © 2019 American Association for Cancer Research. Author Manuscript Published OnlineFirst on July 16, 2019; DOI: 10.1158/1541-7786.MCR-19-0125 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 26 Abstract 27 Protein kinase D1 (PKD1) is a serine/threonine kinase that belongs to the calcium/calmodulin- 28 dependent kinase family, and is involved in multiple mechanisms implicated in tumor 29 progression such as cell motility, invasion, proliferation, protein transport, and apoptosis. While 30 it is expressed in most tissues in the normal state, PKD1 expression may increase or decrease 31 during tumorigenesis, and its role in proliferation is context-dependent and poorly understood. In 32 this review, we present and discuss the current landscape of studies investigating the role of 33 PKD1 in the proliferation of both cancerous and normal cells. Indeed, as a potential therapeutic 34 target, deciphering whether PKD1 exerts a pro- or anti-proliferative effect, and under what 35 conditions, is of paramount importance. 2 Downloaded from mcr.aacrjournals.org on October 1, 2021. © 2019 American Association for Cancer Research. Author Manuscript Published OnlineFirst on July 16, 2019; DOI: 10.1158/1541-7786.MCR-19-0125 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 36 Introduction 37 38 PKD1, also called PKCµ, is a serine/threonine kinase that belongs to the PKD family, a 39 subgroup of the calcium/calmodulin-dependent kinase (CAMK) family (1). PKD1 is a 912 40 amino acid residue protein with an apparent molecular weight of 115 kDa which contains a 41 carboxy-terminus catalytic domain and a regulatory domain at the amino-terminus. The latter 42 regulates the catalytic activity of PKD1 by maintaining the protein in an inactive state through an 43 auto-inhibitory mechanism exerted towards the catalytic domain (2). PKD1 can be activated by a 44 wide variety of extracellular stimuli including growth factors, vasoactive peptides, chemokines, 45 neuropeptides, phorbol esters, and others. To date, the best characterized signalling pathway 46 responsible for the activation of PKD1 involves the activation of phospholipases Cβ or γ (PLCβ 47 or PLCγ) (3). These proteins synthesize inositol-triphosphate (IP3) and diaglycerol (DAG) which 48 allows the activation of several protein kinase C (PKC) isoforms and their recruitment close to 49 PKD1. Once nearby, PKCs phosphorylate PKD1 onto two serine residues (738 and 742, or 744 50 and 748, human or murine numbering, respectively) localized in its activation loop leading to the 51 stimulation of the catalytic domain and its autophosphorylation onto its serine 910 (or 916 for 52 murine PKD1) residue (4). Activated PKD1 thus translocates into different cellular 53 compartments modulating its targets. The wide diversity of its substrates makes PKD1 a main 54 actor in several biological processes such as cell proliferation, migration, invasion, apoptosis, 55 angiogenesis, cardiac contraction, and immune regulation (5). In this context, its dysregulation 56 (over- or under-expression) was shown to be associated to diverse pathologies such as 57 inflammation, cardiac hypertrophy, and cancer (6). However, it remains largely unknown what 58 regulates PKD1 gene (prkd1) expression in tumors. PKD1 gene promoter was shown to be either 3 Downloaded from mcr.aacrjournals.org on October 1, 2021. © 2019 American Association for Cancer Research. Author Manuscript Published OnlineFirst on July 16, 2019; DOI: 10.1158/1541-7786.MCR-19-0125 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 59 activated by the oncogenic KRas-NF-κB pathway increasing the expression of PKD1 in 60 pancreatic cancer cells (7) or inhibited by beta-catenin in prostate cancer (8). It was also shown 61 to be the target of epigenetic methylation decreasing PKD1 expression in some breast tumor cells 62 (9-11). These different molecular mechanisms lead to tumor tissue specific PKD1 mRNA 63 expression profiles According to TCGA data, PKD1 mRNAs are mostly expressed in prostate 64 cancer and melanoma. (Figure 1). Also, the data relative to 11 studies [Breast Invasive 65 Carcinoma, Colorectal Adenocarcinoma, Head and Neck Squamous Cell Carcinoma, Kidney 66 Renal Clear Cell Carcinoma, Kidney Renal Papillary Cell Carcinoma, Lung Adenocarcinoma, 67 Lung Squamous Cell Carcinoma, Pancreatic Adenocarcinoma, Prostate Adenocarcinoma, Skin 68 Cutaneous Melanoma, Stomach Adenocarcinoma (TCGA, PanCancer Atlas)], has shown PKD1 69 mRNA levels to be upregulated by 1.8 % (pancreas) to 18 % (lung adenocarcinoma) with a mean 70 value of 7.8 % (Additional files 1 to 8: Figures S1 to S8). Moreover, analysis of the prkd1 gene 71 reveals that only 4 % of the tumors analysed (206 patients over 5615) carry a mutation or a copy 72 number alteration in the 11 mentioned above TCGA studies (Figure 2). Taken together, these 73 results suggest, at least for tumors with the lowest upregulated values, that a dysregulated PKD1 74 activity may certainly play a more significant role in tumor progression than its gene 75 overexpression or amplification. 76 Although PKD1 seems to play an essential role in oncogenesis and is activated by a large variety 77 of stimuli, especially by many growth factors, it has a complex relationship with cell 78 proliferation both in normal and cancer cells. In fact, the specificity of the role of PKD1 with 79 regards to cell proliferation depends not only on the tissue type but also on the phenotype 80 (normal vs tumor) since PKD1 has been described to be either pro-proliferative or anti- 81 proliferative (Table 1). Moreover, this complexity drastically increases when, for a given cell 4 Downloaded from mcr.aacrjournals.org on October 1, 2021. © 2019 American Association for Cancer Research. Author Manuscript Published OnlineFirst on July 16, 2019; DOI: 10.1158/1541-7786.MCR-19-0125 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 82 type, some controversial data exist. However, increasing data described PKD1 activity as 83 affecting tumor behaviour both in vitro and in vivo through its ability to regulate cell 84 proliferation making PKD1 a putative pertinent pharmacological target in oncology. In this 85 context, it becomes obviously and urgently crucial to have a clear knowledge of its role in cell 86 proliferation. Therefore, this review aims to list the major data existing to date concerning the 87 pro- or anti-proliferative effects of PKD1 and tries to bring elements of discussion to explain, 88 when necessary, potentially contradictory results. 89 90 PKD1 stimulates angiogenesis, a key determinant in cancer development. 91 Angiogenesis is the process by which new blood vessels are formed and is of pivotal importance 92 in processes such as wound healing and embryonic vascular development (12). It also plays a 93 fundamental role in tumor growth and metastasis (13). It provides tumors with oxygen and 94 nutrients, crucial for their developments and also helps in discarding tumor metabolites (13). 95 Inhibition of angiogenesis has thus been regarded as a valuable new approach to cancer therapy 96 (14). A number of stimulators and inhibitors regulate angiogenesis (15). In the case of PKD1, a 97 consensus exists with regard to its pro-angiogenic and thus pro-proliferative role whatever the 98 cell model (endothelial progenitor cells (EPCs) or cell lines) or the species (human or even 99 zebrafish). VEGF, a major component of angiogenesis under both physiological and pathological 100 conditions, induces the phosphorylation of PKD1 in human umbilical vein endothelial cells 101 (HUVEC) and bovine aortic endothelial cells (BAEC) (16) and EPCs (17). This occurs within 102 minutes upon binding of VEGF to its receptor, VEGFR2, through a PLCγ/PKCα-dependent 103 signaling pathway (16). VEGF-stimulated ERK1/2 phosphorylation and DNA synthesis in 104 HUVEC (16), and VEGF-induced microvessels sprouting from mouse aortic rings (18) were 5 Downloaded from mcr.aacrjournals.org on October 1, 2021. © 2019 American Association for Cancer Research. Author Manuscript Published OnlineFirst on July 16, 2019; DOI: 10.1158/1541-7786.MCR-19-0125 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 105 markedly inhibited by PKD1 knockdown and PKD1 kinase negative mutant expression, 106 respectively, making PKD1 a pro-proliferative protein in endothelial cells. As previously 107 mentioned, histone deacetylases (HDAC) help control gene expression by regulating the 108 acetylation state of the chromatin. VEGF stimulates HDAC7 and HDAC5 phosphorylation and 109 their nucleocytoplasmic shuttling through a PKD1-dependent signaling pathway (17-19). Once 110 phosphorylated and in the cytosolic compartment, HDAC7 is localized away from its substrates 111 promoting gene expression leading to cell proliferation.
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