Protein kinase D-mediated phosphorylation at Ser99 regulates localization of p21-activated kinase 4

Bastea, Ligia I.; Döppler, Heike; Pearce, Sarah E.; Durand, Nisha; Spratley, Samantha J.; Störz, Peter

doi:10.1042/bj20130281

Cited by 21 publications

(22 citation statements)

References 38 publications

(67 reference statements)

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“…Our finding that CRT0066101, a PKD inhibitor, could completely inhibit CCK-8-stimulated PKD activation, but only partially inhibit CCK-8-stimulated PAK4 phosphorylation, demonstrates that CCK-8 stimulates PAK4 activation by both PKD-dependent and PKD-independent cascades. Similar to this finding, PKD activation has been shown to regulate cofilin-driven actin reorganization and cell migration through a PAK4-LIMK-cofilin mechanism (4,19,67).…”

Section: Discussionsupporting

confidence: 65%

“…Previous results report that the PAK family can be activated by a number of different signaling cascades (4,19,39,49,64,80); however, there is no information on the signaling cascades by which GI hormones/neurotransmitters activate Group-II PAKs, including PAK4. Our finding that CRT0066101, a PKD inhibitor, could completely inhibit CCK-8-stimulated PKD activation, but only partially inhibit CCK-8-stimulated PAK4 phosphorylation, demonstrates that CCK-8 stimulates PAK4 activation by both PKD-dependent and PKD-independent cascades.…”

Section: Discussionmentioning

confidence: 99%

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P21-activated kinase 4 in pancreatic acinar cells is activated by numerous gastrointestinal hormones/neurotransmitters and growth factors by novel signaling, and its activation stimulates secretory/growth cascades

Ramos-Álvarez

Jensen

2018

American Journal of Physiology-Gastrointestinal and Liver Physi

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p21-activated kinases (PAKs) are highly conserved serine/threonine protein kinases, which are divided into two groups: group-I (PAKs1-3) and group-II (PAKs4-6). In various tissues, Group-II PAKs play important roles in cytoskeletal dynamics and cell growth as well as neoplastic development/progression. However, little is known about Group-II PAK's role in a number of physiological events, including their ability to be activated by gastrointestinal (GI) hormones/neurotransmitters/growth factors (GFs). We used rat pancreatic acini to explore the ability of GI hormones/neurotransmitters/GFs to activate Group-II-PAKs and the signaling cascades involved. Only PAK4 was detected in pancreatic acini. PAK4 was activated by endothelin, secretagogues-stimulating phospholipase C (bombesin, CCK-8, and carbachol), by pancreatic GFs (insulin, insulin-like growth factor 1, hepatocyte growth factor, epidermal growth factor, basic fibroblast growth factor, and platelet-derived growth factor), and by postreceptor stimulants (12-O-tetradecanoylphobol-13-acetate and A23187 ). CCK-8 activation of PAK4 required both high- and low-affinity CCK-receptor state activation. It was reduced by PKC-, Src-, p44/42-, or p38-inhibition but not with phosphatidylinositol 3-kinase-inhibitors and only minimally by thapsigargin. A protein kinase D (PKD)-inhibitor completely inhibited CCK-8-stimulated PKD-activation; however, stimulated PAK4 phosphorylation was only inhibited by 60%, demonstrating that it is both PKD-dependent and PKD-independent. PF-3758309 and LCH-7749944, inhibitors of PAK4, decreased CCK-8-stimulated PAK4 activation but not PAK2 activation. Each inhibited ERK1/2 activation and amylase release induced by CCK-8 or bombesin. These results show that PAK4 has an important role in modulating signal cascades activated by a number of GI hormones/neurotransmitters/GFs that have been shown to mediate both physiological/pathological responses in acinar cells. Therefore, in addition to the extensive studies on PAK4 in pancreatic cancer, PAK4 should also be considered an important signaling molecule for pancreatic acinar physiological responses and, in the future, should be investigated for a possible role in pancreatic acinar pathophysiological responses, such as in pancreatitis. NEW & NOTEWORTHY This study demonstrates that the only Group-II p21-activated kinase (PAK) in rat pancreatic acinar cells is PAK4, and thus differs from islets/pancreatic cancer. Both gastrointestinal hormones/neurotransmitters stimulating PLC and pancreatic growth factors activate PAK4. With cholecystokinin (CCK), activation is PKC-dependent/-independent, requires both CCK-R affinity states, Src, p42/44, and p38 activation. PAK4 activation is required for CCK-mediated p42/44 activation/amylase release. These results show PAK4 plays an important role in mediating CCK physiological signal cascades and suggest it may be a target in pancreatic acinar diseases besides cancer.

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Section: Discussionsupporting

confidence: 65%

Section: Discussionmentioning

confidence: 99%

P21-activated kinase 4 in pancreatic acinar cells is activated by numerous gastrointestinal hormones/neurotransmitters and growth factors by novel signaling, and its activation stimulates secretory/growth cascades

Ramos-Álvarez

Jensen

2018

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…4A), a type 2 p21-activated kinase. Serine 474 in the PAK4 kinase domain can be auto-phosphorylated or phosphorylated by a number of different kinases to constitute the “active” form of PAK4 (16, 17). PAK4 appears to play a functional role in suppressing senescence in glioblastoma, since treating cells with the ATP-competitive PAK4 inhibitor PF-03758309 increased SA-β-gal staining in U87MG cells in 2D culture and subcutaneous xenografts in vivo (Fig.…”

Section: Resultsmentioning

confidence: 99%

Glioblastomas Require Integrin αvβ3/PAK4 Signaling to Escape Senescence

et al. 2015

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Integrin αvβ3 has been implicated as a driver of aggressive and metastatic disease, and is upregulated during glioblastoma progression. Here we demonstrate that integrin αvβ3 allows glioblastoma cells to counteract senescence through a novel tissue-specific effector mechanism involving recruitment and activation of the cytoskeletal regulatory kinase PAK4. Mechanistically, targeting either αvβ3 or PAK4 led to emergence of a p21-dependent, p53-independent cell senescence phenotype. Notably, glioblastoma cells did not exhibit a similar requirement for either other integrins or additional PAK family members. Moreover, αvβ3/PAK4 dependence was not found to be critical in epithelial cancers. Taken together, our findings established that glioblastomas are selectively addicted to this pathway as a strategy to evade oncogene-induced senescence, with implications that inhibiting the αvβ3/PAK4 signaling axis may offer novel therapeutic opportunities to target this aggressive cancer.

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“…Both, the accumulation of either unphosphorylated or hyperphosphorylated cellular cofilin can lead to decreased migration. Downstream of RhoA, PKD1 affects the cofilin cycle by mediating inactivation of SSH1L [7, 38, 53, 54] and activation of p21-activated kinase 4 (PAK4) which is upstream of LIMK [55, 56]. PKD1 phosphorylates SSH1L in its actin binding motif.…”

Section: Roles Of Pkd Isoforms In Invasive Breast Cancermentioning

confidence: 99%

Functional and therapeutic significance of protein kinase D enzymes in invasive breast cancer

Durand

Borgés

Störz

2015

Cell. Mol. Life Sci.

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The Protein Kinase D (PKD) family members, PKD1, PKD2 and PKD3 constitute a family of serine/threonine kinases that are essential regulators of cell migration, proliferation and protein transport. Multiple types of cancers are characterized by aberrant expression of PKD isoforms. In breast cancer PKD isoforms exhibit distinct expression patterns and regulate various oncogenic processes. In highly-invasive breast cancer, the leading cause of cancer-associated deaths in females, the loss of PKD1 is thought to promote invasion and metastasis, while PKD2 and upregulated PKD3 have been shown to be positive regulators of proliferation, chemoresistance and metastasis. In this review, we examine the differential expression pattern, mechanisms of regulation and contributions made by each PKD isoform to the development and maintenance of invasive breast cancer. In addition, we discuss the potential therapeutic approaches for targeting PKD in this disease.

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Protein kinase D-mediated phosphorylation at Ser99 regulates localization of p21-activated kinase 4

Cited by 21 publications

References 38 publications

P21-activated kinase 4 in pancreatic acinar cells is activated by numerous gastrointestinal hormones/neurotransmitters and growth factors by novel signaling, and its activation stimulates secretory/growth cascades

P21-activated kinase 4 in pancreatic acinar cells is activated by numerous gastrointestinal hormones/neurotransmitters and growth factors by novel signaling, and its activation stimulates secretory/growth cascades

Glioblastomas Require Integrin αvβ3/PAK4 Signaling to Escape Senescence

Functional and therapeutic significance of protein kinase D enzymes in invasive breast cancer

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