p21-activated Kinase-1 Signaling Mediates Cyclin D1 Expression in Mammary Epithelial and Cancer Cells

Balasenthil, Seetharaman; Şahin, Ayşegül; Barnes, Christopher J.; Wang, Rui An; Pestell, Richard G.; Vadlamudi, Ratna K.; Kumar, Rakesh

doi:10.1074/jbc.m309937200

Cited by 196 publications

(164 citation statements)

References 38 publications

(48 reference statements)

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“…Our gain-and loss-of-function results all indicated that PAK1 activity controls cyclin D1 level, consistent with previous reports (Balasenthil et al, 2004). Next, we asked whether it controls cyclin D1 expression through b-catenin signaling.…”

Section: Pak1 Is Required For Proliferation Of Colon Cancer Cellssupporting

confidence: 91%

A Rac1/PAK1 cascade controls β-catenin activation in colon cancer cells

et al. 2011

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P21-activated kinase 1 (PAK1) is associated with colon cancer progression and metastasis, whereas the molecular mechanism remains elusive. Here, we show that downregulation of PAK1 in colon cancer cells reduces total b-catenin level, as well as cell proliferation. Mechanistically, PAK1 directly phosphorylates b-catenin proteins at Ser675 site and this leads to more stable and transcriptional active b-catenin. Corroborating these results, PAK1 is required for full Wnt signaling, and superactivation of b-catenin is achieved by simultaneous knockdown of adenomatous polyposis coli protein and activation of PAK1. Moreover, we show that Rac1 functions upstream of PAK1 in colon cancer cells and contributes to b-catenin phosphorylation and accumulation. We conclude that a Rac1/PAK1 cascade controls b-catenin S675 phosphorylation and full activation in colon cancer cells. Supporting this conclusion, overexpression of PAK1 is observed in 70% of colon cancer samples and is correlated with massive b-catenin accumulation.

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Section: Pak1 Is Required For Proliferation Of Colon Cancer Cellssupporting

confidence: 91%

A Rac1/PAK1 cascade controls β-catenin activation in colon cancer cells

et al. 2011

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“…Of the PAK family, PAK1 has been implicated in both breast cancer and colon cancer progression, [24][25][26] while PAK4 was found to be overexpressed in 78% of a variety of human cancer cell lines. 12 PAK6 was first identified based on its expression in the prostate and testes, and later it was also shown to be highly expressed in the brain.…”

Section: Discussionmentioning

confidence: 99%

P21‐activated kinase 5 is overexpressed during colorectal cancer progression and regulates colorectal carcinoma cell adhesion and migration

Gong

Wang

et al. 2009

Intl Journal of Cancer

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P21-activated kinase 5 (PAK5) is the recently identified member of the group B p21-activated kinase (PAK) family which are effectors of the small GTPase Cdc42 and Rac1, known to regulate cell motility and activate cell-survival signaling pathways. However, overexpression of PAK5 has not been associated with any cancers so far. Interestingly, we found that PAK5 was overexpressed in a variety of colorectal carcinoma (CRC) cell lines in a Western-blotting examination. Therefore, in this study, we aim to examine the PAK5 expression during CRC progression and to answer if PAK5 is involved in malignant progression of CRC. By immunohistochemistry, our results showed that PAK5 expression was increased with CRC progression through the adenoma to carcinoma sequence, with the most significant increases in invasive and metastatic CRCs (p < 0.0001). Furthermore, increased PAK5 expression was also found with the development of CRC from lower Duke's grades to higher ones (p < 0.01). Moreover, PAK5 was also increased from well to poorly differentiated CRCs (p < 0.01). Using gain and loss of function experiments, we found that PAK5 reduced CRC cell adhesion but promoted their migration on collagen type I. Taken together, our study demonstrated that PAK5 expression increased significantly with malignant progression of CRC and that PAK5 might promote CRC metastasis by regulating CRC cell adhesion and migration. ' UICCKey words: colorectal carcinoma; PAK5; cancer cell adhesion and migration P21-activated kinases (PAKs), a family of serine/threonine kinases, are small GTPase effectors that play important roles in regulating cell shape, movement, proliferation and survival. [1][2][3] PAKs are characterized by a highly conserved amino-terminal Cdc42/ Rac interactive binding (CRIB) domain and a carboxyl terminal kinase domain. [4][5][6] Six human PAKs were identified and divided into two groups based on their amino acid sequences and their functions. Group A PAKs (PAK1, 2 and 3) share 80 to 90% sequence identity within their catalytic domains, whereas the recently identified group B PAKs (PAK4, 5 and 6), show only approximately 50% identity to the kinase domains of the group A PAKs. 6,7 A marked difference between the two PAK groups is the autologous inhibitory sequence in the NH2-terminal regulatory domain found in group A PAKs, with no obvious homologous sequence in group B. 7 Unlike group A PAKs, whose binding of Cdc42 and Rac leads to their activation, Group B PAKs are not strongly activated by GTPase binding. 8 Of the three group B PAKs, PAK4 was the best characterized, involving in cell adhesion, migration, proliferation and activation of cell-survival pathways that lead to protection from apoptosis. 9,10 Our previous study demonstrated that PAK4 regulated integrin avb5-mediated breast carcinoma cell migration. 11 Different PAK family members have different tissue-specific expression patterns. PAK4 was found to be overexpressed in 78% of a variety of human cancer cell lines, 12 whereas PAK5 and PAK6 showed restricted tissue-spe...

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“…The pak1 pathway, starting at the cell surface by growth factor activation of receptors, could also influence cyclin D1 oncogenic functions in breast cancer through an NF-kB-dependent pathway (Balasenthil et al, 2004b).…”

Section: Introductionmentioning

confidence: 99%

Amplification of CCND1 and PAK1 as predictors of recurrence and tamoxifen resistance in postmenopausal breast cancer

et al. 2007

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The 11q13 region is amplified in approximately 15% of all breast tumors. Situated in this region are the cyclin D1 gene (CCND1) and the p-21-activated kinase 1 (PAK1) gene. Both genes encode proteins shown to activate the estrogen receptor (ER), leading to transcription of CCND1 and other ER-responsive genes. Here, we investigate the prognostic and treatment predictive role of CCND1 and PAK1 gene amplification in postmenopausal breast cancer patients randomized to tamoxifen treatment or no adjuvant treatment. Amplification of CCND1 and PAK1, assessed by real-time PCR, was observed in 12.5 and 9.3%, respectively. Amplification of PAK1 was seen in 37% of the CCND1-amplified tumors, indicating coamplification (Po0.001). In ER-positive patients, amplification of at least one of the genes indicated a reduced recurrence-free survival (P=0.025). When response to tamoxifen treatment was analysed, patients with PAK1 amplification showed decreased benefit from the drug (ER+; relative risk ratio (RR)=1.62; 95% confidence interval (CI), 0.47-5.55) compared to patients without amplification (ER+; RR=0.53; 95% CI, 0.32-0.88). This was not evident for CCND1 amplification. We show that PAK1 may be a predictor of tamoxifen resistance and furthermore, we do not discard PAK1 as a potential candidate oncogene in the 11q13 amplicon. In addition, we show that high pak1 protein levels may predict tamoxifen insensitivity.

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p21-activated Kinase-1 Signaling Mediates Cyclin D1 Expression in Mammary Epithelial and Cancer Cells

Cited by 196 publications

References 38 publications

A Rac1/PAK1 cascade controls β-catenin activation in colon cancer cells

A Rac1/PAK1 cascade controls β-catenin activation in colon cancer cells

P21‐activated kinase 5 is overexpressed during colorectal cancer progression and regulates colorectal carcinoma cell adhesion and migration

Amplification of CCND1 and PAK1 as predictors of recurrence and tamoxifen resistance in postmenopausal breast cancer

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