Protein Kinase D Signaling: Multiple Biological Functions in Health and Disease

Rozengurt, Enrique

doi:10.1152/physiol.00037.2010

Cited by 197 publications

(241 citation statements)

References 117 publications

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“…We tested whether cortactin was a direct substrate for aPKCζ/ι by incubating purified GST-tagged human cortactin in the presence of recombinant human aPKCι. Phosphorylation was detected with antibodies raised against cortactin phosphoSer298, which was recently identified as a phosphorylation site for aPKCζ/ι-related PKD (35,36). In higher metazoans, mRNA splicing generates cortactin variants with four, five, or six conserved tandem actin-binding repeats in which repeats 5 and 6 are the most conserved (37).…”

Section: Apkcζ/ι-dependent Phosphorylation Of Cortactin Controls Itsmentioning

confidence: 99%

Control of MT1-MMP transport by atypical PKC during breast-cancer progression

Rossé

Lodillinsky

Fuhrmann

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Dissemination of carcinoma cells requires the pericellular degradation of the extracellular matrix, which is mediated by membrane type 1-matrix metalloproteinase (MT1-MMP). In this article, we report a co-up-regulation and colocalization of MT1-MMP and atypical protein kinase C iota (aPKCι) in hormone receptor-negative breast tumors in association with a higher risk of metastasis. Silencing of aPKC in invasive breast-tumor cell lines impaired the delivery of MT1-MMP from late endocytic storage compartments to the surface and inhibited matrix degradation and invasion. We provide evidence that aPKCι, in association with MT1-MMP-containing endosomes, phosphorylates cortactin, which is present in F-actin-rich puncta on MT1-MMP-positive endosomes and regulates cortactin association with the membrane scission protein dynamin-2. Thus, cell line-based observations and clinical data reveal the concerted activity of aPKC, cortactin, and dynamin-2, which control the trafficking of MT1-MMP from late endosome to the plasma membrane and play an important role in the invasive potential of breast-cancer cells.membrane traffic | actin cytoskeleton | multi-vesicular body | MMP14

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Section: Apkcζ/ι-dependent Phosphorylation Of Cortactin Controls Itsmentioning

confidence: 99%

Control of MT1-MMP transport by atypical PKC during breast-cancer progression

Rossé

Lodillinsky

Fuhrmann

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…PKDs are mainly activated by PKC (23,24). PKDs regulate many cellular functions, such as gene expression, cell adhesion and migration, and protein transport at the trans-Golgi network, etc.…”

mentioning

confidence: 99%

“…PKDs regulate many cellular functions, such as gene expression, cell adhesion and migration, and protein transport at the trans-Golgi network, etc. (23,24). PKD1 is an important sensor of oxidative stress (25,26), which is activated by ROS-PKCδ and subsequently induces NF-κB activity.…”

mentioning

confidence: 99%

Protein kinase D1 is essential for Ras-induced senescence and tumor suppression by regulating senescence-associated inflammation

Wang

Han

Wang

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Oncogene-induced senescence (OIS) is an initial barrier to tumor development. Reactive oxygen species (ROS) is critical for oncogenic Ras OIS, but the downstream effectors to mediate ROS signaling are still relatively elusive. Senescent cells develop a senescence-associated secretory phenotype (SASP). However, the mechanisms underlying the regulation of the SASP are largely unknown. Here, we identify protein kinase D1 (PKD1) as a downstream effector of ROS signaling to mediate Ras OIS and SASP. PKD1 is activated by oncogenic Ras expression and PKD1 promotes Ras OIS by mediating inflammatory cytokines interleukin-6 (IL-6) and interleukin-8 (IL-8) via modulation of NF-κB activity. We demonstrate that ROSprotein kinase Cδ (PKCδ)-PKD1 axis is essential for the establishment and maintenance of IL-6/IL8 induction. In addition, ablation of PKD1 causes the bypass of Ras OIS, and promotes cell transformation and tumorigenesis. Together, these findings uncover a previously unidentified role of ROS-PKCδ-PKD1 pathway in Ras OIS and SASP regulation.C ellular senescence is a permanent cell growth arrest state triggered either by telomere attrition (replicative senescence), or by many other stimuli, such as DNA damage, oxidative stress, and oncogenes activation, etc., without any detectable telomere shortening (premature senescence) (1). Oncogene-induced senescence (OIS) is of particular interest. OIS indeed occurs in premalignant human tumors and represents an initial barrier for cancer development in vivo (2). One well-characterized type of OIS is that induced by oncogenic Ras. Ras expression in normal primary cells induces premature senescence (3). ROS plays an important role in Ras OIS. ROS levels increase in Ras OIS, and ROS elimination prevent Ras OIS (4). Seladin-1 was identified as a downstream effector of ROS to mediate Ras OIS (5). Several positive ROS-generating feedback loops, such as ROS-protein kinase Cδ (PKCδ) loop (6), mitochondrial dysfunctional signaling (7), and DDB2-mediated pathway (8), were proposed to contribute to elevated ROS levels in Ras OIS. Despite steady progress in probing the roles of ROS in senescence, however, most of studies focus on the links between ROS and the p53, p16, and DNA damage response (DDR) pathways, little is known about other mechanisms that ROS might mediate Ras OIS.Senescent cells develop a senescence-associated secretory phenotype (SASP) by secretion of numerous cytokines, chemokines, and other proteins (9, 10). SASP have multiple biological effects depending on the physiological context. Some SASP factors such as IL-6/IL-8 and others can suppress early tumor formation either by reinforcing senescence in an autocrine fashion (11, 12), or by stimulating the immune system to clear premalignant senescent cells in a paracrine manner (13). SASP also can facilitate tissue repair (14). On the other hand, SASP can promote tumor growth (15). Moreover, many proinflammatory factors in SASP might be an important source of the low-level chronic inflammation in aged mammalian tissues, henc...

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“…In most cases, PKD1 phosphorylates a sequence characterized by L/V/I at position -5 and R/K at position-3 PKD1, dopamine D1 receptor, and cocaine addiction N Wang et al (Rozengurt, 2011). The S421 identified in the present study does not fit the classical consensus phosphorylation sites for PKD1 (Supplementary Figure 1c).…”

Section: Discussionmentioning

confidence: 54%

“…To date, PKD1 is the best-characterized isoform of this family (Rozengurt et al, 2005;Steinberg, 2012). PKD1 has a vital role in various important biological processes, including cell proliferation and differentiation, vesicle trafficking and secretion, immune regulation and cardiac hypertrophy, and contraction (Rozengurt, 2011). In the nervous system, we first found that PKD1 has an important role in inflammatory heat hyperalgesia through an interaction with transient receptor potential vanilloid 1 (Wang et al, 2004;Zhu et al, 2008).…”

Section: Introductionmentioning

confidence: 97%

Protein Kinase D1-Dependent Phosphorylation of Dopamine D1 Receptor Regulates Cocaine-Induced Behavioral Responses

Wang

Zhang

et al. 2013

Neuropsychopharmacol

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The dopamine (DA) D1 receptor (D1R) is critically involved in reward and drug addiction. Phosphorylation-mediated desensitization or internalization of D1R has been extensively investigated. However, the potential for upregulation of D1R function through phosphorylation remains to be determined. Here we report that acute cocaine exposure induces protein kinase D1 (PKD1) activation in the rat striatum, and knockdown of PKD1 in the rat dorsal striatum attenuates cocaine-induced locomotor hyperactivity. Moreover, PKD1-mediated phosphorylation of serine 421 (S421) of D1R promotes surface localization of D1R and enhances downstream extracellular signal-regulated kinase signaling in D1R-transfected HEK 293 cells. Importantly, injection of the peptide Tat-S421, an engineered Tat fusion-peptide targeting S421 (Tat-S421), into the rat dorsal striatum inhibits cocaine-induced locomotor hyperactivity and injection of Tat-S421 into the rat hippocampus or the shell of the nucleus accumbens (NAc) also inhibits cocaine-induced conditioned place preference (CPP). However, injection of Tat-S421 into the rat NAc shell does not establish CPP by itself and injection of Tat-S421 into the hippocampus does not influence spatial learning and memory. Thus, targeting S421 of D1R represents a promising strategy for the development of pharmacotherapeutic treatments for drug addiction and other disorders that result from DA imbalances.

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Protein Kinase D Signaling: Multiple Biological Functions in Health and Disease

Cited by 197 publications

References 117 publications

Control of MT1-MMP transport by atypical PKC during breast-cancer progression

Control of MT1-MMP transport by atypical PKC during breast-cancer progression

Protein kinase D1 is essential for Ras-induced senescence and tumor suppression by regulating senescence-associated inflammation

Protein Kinase D1-Dependent Phosphorylation of Dopamine D1 Receptor Regulates Cocaine-Induced Behavioral Responses

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