p21-activated kinases in human cancer

  title={p21-activated kinases in human cancer},
  author={Ratna K. Vadlamudi and Rakesh Kumar},
  journal={Cancer and Metastasis Reviews},
A balance between proliferation, differentiation, migration and death of cells is critical for the normal development of an organism. Perturbations of this balance can contribute to cancer development. The p21-activated serine/threonine kinases (Paks) play an important role in a variety of cellular functions including cell morphogenesis, motility, survival, angiogenesis, and mitosis. Paks were initially identified as an effector molecules of RHO GTPases; however, recent evidence that they can… 

Development of p21 activated kinase-targeted multikinase inhibitors that inhibit thyroid cancer cell migration.

2 new multikinase inhibitors with anti-PAK activity are developed that may serve as scaffolds for further compound development targeting this progression-related thyroid cancer target.

p21-activated kinase 1 determines stem-like phenotype and sunitinib resistance via NF-κB/IL-6 activation in renal cell carcinoma

It is unraveled that oncogenic activation of PAK1 defines an important mechanism for maintaining stem-like phenotype and sunitinib resistance through NF-κB/IL-6 activation in RCC, lendingPAK1-mediated NF-kkB/ IL-6activation considerable appeal as novel pharmacological therapeutic targets against sunit inib resistance.

Overexpression of p21-activated kinase 1 promotes endometrial cancer progression.

Results suggest that Pak1 plays important roles at multiple stages of EC progression, including cell proliferation, migration, invasion and anchorage-independent growth in vitro.

Nuclear Localization and Chromatin Targets of p21-activated Kinase 1*

Investigations provide proof-of-principle evidence that Pak1 could influence the expression of its putative chromatin targets in both a positive and a negative manner, opening new avenues to further the search for nuclear Pak1 functions and identify putative Pak1-interacting nuclear proteins.

CRIPak, a novel endogenous Pak1 inhibitor

The findings suggest that CRIPak is a novel negative regulator of the Pak1 and has a role in the modulation of Pak1-mediated ER transactivation in breast cancer cells.

Group I p21-activated kinases regulate thyroid cancer cell migration and are overexpressed and activated in thyroid cancer invasion.

PAK1 regulates thyroid cancer cell motility, and PAK1 and pPAK levels are increased in PTC invasive fronts, which implicate PAKs as regulators of thyroid cancer invasion.

Emodin inhibits tumor cell migration through suppression of the phosphatidylinositol 3-kinase-Cdc42/Rac1 pathway

Data from this study suggest that emodin inhibits human cancer cell migration by suppressing the PI3K-Cdc42/Rac1 signaling pathway.

RACK1 promotes breast carcinoma proliferation and invasion/metastasis in vitro and in vivo

RACK1 is an independent prognosis-related factor and promotes breast carcinoma proliferation and invasion/metastasis in vitro and in vivo and can be inhibited by the addition of Rho-kinase inhibitor.



Emerging functions of p21‐activated kinases in human cancer cells

The current knowledge of the Paks family with respect to emerging cellular functions and possible contributions to cancer is summarized.

Requirement for PAK4 in the Anchorage-independent Growth of Human Cancer Cell Lines*

It is demonstrated that PAK4 is frequently overexpressed in human tumor cell lines of various tissue origins and identified serine (Ser-474) as the likely autophosphorylation site in the kinase domain of PAK 4 in vivo, and suggested thatPAK4 activity is required for Ras-driven, anchorage-independent growth.

Regulation of Microfilament Reorganization and Invasiveness of Breast Cancer Cells by Kinase Dead p21-activated Kinase-1*

It is demonstrated that overexpression of a kinase dead K299R PAK1 mutant leads to suppression of motile phenotypes as well as invasiveness of cells both in the absence or presence of exogenous heregulin-β1, and downstream pathways have a role in the development and maintenance of invasive phenotypes in breast cancer cells.

Endogenous, hyperactive Rac3 controls proliferation of breast cancer cells by a p21-activated kinase-dependent pathway.

It is shown that endogenous, hyperactive Rac3 is present in highly proliferative human breast cancer-derived cell lines and tumor tissues and suggests an important role for Rac3 and Pak in tumor growth.

p21-Activated Kinase 1 (Pak1) Regulates Cell Motility in Mammalian Fibroblasts

Results suggest that Pak1 affects the phosphorylation state of MLC, thus linking this kinase to a molecule that directly affects cell movement.

Etk/Bmx Tyrosine Kinase Activates Pak1 and Regulates Tumorigenicity of Breast Cancer Cells*

The role of Etk in mammary development and tumorigenesis is characterized and the functional interactions between Etk and Pak1 are explored, showing that Etk directly associates with Pak1 via its N-terminal pleckstrin homology domain and also phosphorylates Pak1 on tyrosine residues.

A Role for P21-Activated Kinase in Endothelial Cell Migration

The results demonstrate that although PAK is not required for extension of lamellipodia, it has substantial effects on cell adhesion and contraction, and suggest a model in which PAK plays a role coordinating the formation of new adhesions at the leading edge with contraction and detachment at the trailing edge.

Heregulin Regulates Cytoskeletal Reorganization and Cell Migration through the p21-activated Kinase-1 via Phosphatidylinositol-3 Kinase*

A role of PI-3 kinase/PAK1-dependent reorganization of the cortical actin cytoskeleton in HRG-mediated increased cell migration is suggested, and these changes may have significant consequences leading to enhanced invasion by breast cancer cells.

Regulatable Expression of p21-activated Kinase-1 Promotes Anchorage-independent Growth and Abnormal Organization of Mitotic Spindles in Human Epithelial Breast Cancer Cells*

This study provides evidence to suggest a close correlation between the status of Pak1 kinase activity and base-line invasiveness of human breast cancer cells and breast tumor grades and develops human epithelial MCF-7 clones that overexpressed the kinase-active T423E Pak1 mutant under an inducible tetracycline promoter.

Dysregulation of phosphatidylinositol 3‐kinase and downstream effectors in human breast cancer

It is concluded that aberrant mitogenic signaling in human breast cancer in vivo involves Pak, p38 MAPK and MAPKAPK2 downstream of PI3‐K, but neither of PKB or p70 S6K, and it is proposed that this pathway may serve as a useful targeting nexus for investigation of small molecule inhibitors inhuman breast cancer.