Pak1 Kinase Links ErbB2 to β-Catenin in Transformation of Breast Epithelial Cells

Arias-Romero, Luis E.; Villamar-Cruz, Olga; Huang, Min; Hoeflich, Klaus P.; Chernoff, Jonathan

doi:10.1158/0008-5472.can-12-4453

Cited by 68 publications

(74 citation statements)

References 45 publications

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“…In contrast to these findings, previous studies showed that deletion of either Pak1 or Pak3 is tolerated, and mice lacking either of these genes do not display significant vascular defects (12). These results are consistent with the fact that Pak2 is the main isoform expressed in ECs (35) and the idea that Pak1 and Pak2 have distinct and often opposing roles in mediating various cellular events, as has been suggested by a number of recent studies (36)(37)(38).…”

Section: Discussionsupporting

confidence: 84%

p21-Activated Kinase 2 Regulates Endothelial Development and Function through the Bmk1/Erk5 Pathway

Radu

Lyle²,

Hoeflich³

et al. 2015

Molecular and Cellular Biology

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c p21-activated kinases (Paks) have been shown to regulate cytoskeleton rearrangements, cell proliferation, attachment, and migration in a variety of cellular contexts, including endothelial cells. However, the role of endothelial Pak in embryo development has not been reported, and currently, there is no consensus on the endothelial function of individual Pak isoforms, in particular p21-activated kinase 2 (Pak2), the main Pak isoform expressed in endothelial cells. In this work, we employ genetic and molecular studies that show that Pak2, but not Pak1, is a critical mediator of development and maintenance of endothelial cell function. Endothelial depletion of Pak2 leads to early embryo lethality due to flawed blood vessel formation in the embryo body and yolk sac. In adult endothelial cells, Pak2 depletion leads to severe apoptosis and acute angiogenesis defects, and in adult mice, endothelial Pak2 deletion leads to increased vascular permeability. Furthermore, ubiquitous Pak2 deletion is lethal in adult mice. We show that many of these defects are mediated through a newly unveiled Pak2/Bmk1 pathway. Our results demonstrate that endothelial Pak2 is essential during embryogenesis and also for adult blood vessel maintenance, and they also pinpoint the Bmk1/ Erk5 pathway as a critical mediator of endothelial Pak2 signaling.T he p21-activated kinases (Paks) are evolutionarily conserved serine/threonine kinases that act downstream of the Rho family GTPases, Rac1 and Cdc42, to regulate numerous cellular processes. p21-activated kinase 1 (Pak1) to Pak3, the group I Paks, are expressed in numerous tissues with Pak1 being predominantly expressed in brain, muscle, gastrointestinal tract, and thyroid and Pak3 being predominantly expressed in brain (1, 2). Compared to the more restricted expression of Pak1 and Pak3, Pak2 is ubiquitously expressed (3-9). Group I Pak family members share a high degree of homology (3), but they may play distinct roles as observed by the significantly different phenotypes of knockout (KO) animal models. While Pak1 KO and Pak3 KO mice are viable (10, 11), Pak2 KO mice are embryonic lethal at embryonic day 8.5 (E8.5) due to multiple developmental abnormalities, including cardiovascular defects (12).The role of Pak in endothelial cell (EC) signaling has been studied in animal models (5, 13) and cultured cells (6,10,14,15). Pak signaling is critical in regulating EC attachment, migration, and lumen formation (4-9). Furthermore, Paks have been implicated in maintaining the integrity of the endothelial barrier, but conflicting data implicate various Pak isoforms as both positive and negative regulators of maintaining barrier function (5, 13, 14, 16).A few in vivo studies have specifically implicated Pak2 in vascular pathways. A study in Danio rerio showed that pak2a, one of two Pak2 orthologs in this organism, plays an important role in cerebral vascular maintenance (5). In this study, chemical mutagenesis of the pak2a gene and pak2a-targeting morpholinos caused cerebral hemorrhage, implicating this...

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Section: Discussionsupporting

confidence: 84%

p21-Activated Kinase 2 Regulates Endothelial Development and Function through the Bmk1/Erk5 Pathway

Radu

Lyle²,

Hoeflich³

et al. 2015

Molecular and Cellular Biology

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“…PAKs are overexpressed or/and hyperactivated in variety of human malignancies including bladder, melanoma, breast, prostate, colorectal, and ovarian carcinoma (13). Importantly, compelling genetic and pharmacologic evidence exists that shows that inhibiting group I PAKs can block transformation by oncogenic drivers such as ERBB2 (14), and K-RAS (15). Thus, this kinase is a well-validated anti-cancer target.…”

Section: Introductionmentioning

confidence: 99%

Molecular Pathways: Targeting the Kinase Effectors of RHO-Family GTPases

Prudnikova

Rawat

Chernoff

2015

Clinical Cancer Research

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RHO GTPases, members of the RAS superfamily of small GTPases, are adhesion and growth-factor activated molecular switches that play important roles in tumor development and progression. When activated, RHO-family GTPases such as RAC1, CDC42, and RHOA, transmit signals by recruiting a variety of effector proteins, including the protein kinases PAK, ACK, MLK, MRCK, and ROCK. Genetically-induced loss of RHO function impedes transformation by a number of oncogenic stimuli, leading to an interest in developing small molecule inhibitors that either target RHO GTPases directly, or that target their downstream protein kinase effectors. Although inhibitors of RHO GTPases and their downstream signaling kinases have not yet been widely adopted for clinical use, their potential value as cancer therapeutics continues to facilitate pharmaceutical research and development and is a promising therapeutic strategy.

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“…Pak1-deleted tumors had reduced ERK1/2 and Akt activation and expressed less ␤-catenin. Additionally, treatment of subcutaneous BT474 cell xenografts with the Pak1 inhibitor PF-3758309 completely blocked tumor growth, whereas the ␤-catenin-TCF4 inhibitor iCRT14 was without effect (90). The Cdc42 regulated kinase Pak4, which signals distinctly from Paks 1-3, may also play a role in mammary gland tumorigenesis.…”

Section: Rho Effectors In Mammary Gland Tumorigenesis and Metastasismentioning

confidence: 98%

“…Expression of the Pak1 autoinhibitory domain in MDA-MB-631 cells, which blocks activation of Paks 1-3, reduced subcutaneous tumor growth and inhibited ERK and Akt activation in SCID mice (89). Moreover, Pak1 deletion significantly delayed tumorigenesis in MMTV-Neu mice (90). Pak1-deleted tumors had reduced ERK1/2 and Akt activation and expressed less ␤-catenin.…”

Section: Rho Effectors In Mammary Gland Tumorigenesis and Metastasismentioning

confidence: 99%

Minireview: Mouse Models of Rho GTPase Function in Mammary Gland Development, Tumorigenesis, and Metastasis

Zuo

Ulu

et al. 2016

Molecular Endocrinology

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Ras homolog (Rho) family small GTPases are critical regulators of actin cytoskeletal organization, cell motility, proliferation, and survival. Surprisingly, the large majority of the studies underlying our knowledge of Rho protein function have been carried out in cultured cells, and it is only recently that researchers have begun to assess Rho GTPase regulation and function in vivo. The purpose of this review is to evaluate our current knowledge of Rho GTPase function in mouse mammary gland development, tumorigenesis and metastasis. Although our knowledge is still incomplete, these studies are already uncovering important themes as to the physiological roles of Rho GTPase signaling in normal mammary gland development and function. Essential contributions of Rho proteins to breast cancer initiation, tumor progression, and metastatic dissemination have also been identified.

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Pak1 Kinase Links ErbB2 to β-Catenin in Transformation of Breast Epithelial Cells

Cited by 68 publications

References 45 publications

p21-Activated Kinase 2 Regulates Endothelial Development and Function through the Bmk1/Erk5 Pathway

p21-Activated Kinase 2 Regulates Endothelial Development and Function through the Bmk1/Erk5 Pathway

Molecular Pathways: Targeting the Kinase Effectors of RHO-Family GTPases

Minireview: Mouse Models of Rho GTPase Function in Mammary Gland Development, Tumorigenesis, and Metastasis

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