Emerging from the Pak: the p21-activated protein kinase family

Sells, Mary Ann; Chernoff, Jonathan

doi:10.1016/s0962-8924(97)01003-9

Cited by 287 publications

(274 citation statements)

References 51 publications

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“…[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.…”

Section: Uiccmentioning

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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Section: Uiccmentioning

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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“…The kinase moieties of the class III myosins are members of the germinal center kinase subfamily of the Ste20 group kinases (Sells and Chernoff, 1997;Dan et al, 2000). These kinase/myosin chimeras now constitute their own germinal center kinase subfamily VII (Dan et al, 2000).…”

Section: Class III Myosinsmentioning

confidence: 99%

Myo3A, One of Two Class III Myosin Genes Expressed in Vertebrate Retina, Is Localized to the Calycal Processes of Rod and Cone Photoreceptors and Is Expressed in the Sacculus

Dosé

Hillman

Wong

et al. 2003

MBoC

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The striped bass has two retina-expressed class III myosin genes, each composed of a kinase, motor, and tail domain. We report the cloning, sequence analysis, and expression patterns of the long (Myo3A) and short (Myo3B) class III myosins, as well as cellular localization and biochemical characterization of the long isoform, Myo3A. Myo3A (209 kDa) is expressed in the retina, brain, testis, and sacculus, and Myo3B (155 kDa) is expressed in the retina, intestine, and testis. The tails of these two isoforms contain two highly conserved domains, 3THDI and 3THDII. Whereas Myo3B has three IQ motifs, Myo3A has nine IQ motifs, four in its neck and five in its tail domain. Myo3A localizes to actin filament bundles of photoreceptors and is concentrated in the calycal processes. An anti-Myo3A antibody decorates the actin cytoskeleton of rod inner/outer segments, and this labeling is reduced by the presence of ATP. The ATP-sensitive actin association is a feature characteristic of myosin motors. The numerous IQ motifs may play a structural or signaling role in the Myo3A, and its localization to calycal processes indicates that this myosin mediates a local function at this site in vertebrate photoreceptors. INTRODUCTIONThe asymmetrical shapes of the rods and cones of the vertebrate retina are specialized to mediate photon detection and signal transmission. At the distal ends are the outer segments, which are composed of stacks of photopigmentbearing membranous disks surrounded by the plasma membrane. Progressively proximal to the outer segment are the mitochondrion-packed ellipsoid, the endoplasmic reticulum-and Golgi-rich myoid, the perinuclear region, the axon, and the synapse. The outer segment is connected to the rest of the cell by the narrow connecting cilium, through which metabolic fuels and newly synthesized proteins are transported. Although they maintain highly specialized shapes, photoreceptors are not static. Elaborately choreographed morphogenetic movements establish the specialized shapes of photoreceptors during development. Once formed, photoreceptors undergo outer segment turnover throughout life. This turnover is mediated by the daily addition of new disks to the base of the outer segment and the shedding of effete disks from the tip (Young, 1976). Disk addition requires transport of newly synthesized materials from the perinuclear and myoid regions to and through the connecting cilium. More dramatic photoreceptor motility occurs during retinomotor movements of lower vertebrates; light onset induces cone myoids to contract and rod myoids to elongate, whereas dark onset induces opposite movements (Burnside, 1978).Several observations suggest that the actin cytoskeleton plays an important role in photoreceptor motile processes. Photoreceptors are richly endowed with actin filaments deployed in distinct populations and likely to reflect specialized functional roles. Filamentous actin is concentrated in the distal connecting cilium of the outer segment (Chaitin et al., 1984;Wolfrum and Schmitt, 2000) and throu...

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“…PAKs are characterized by a highly conserved amino-terminal Cdc42/Rac interactive binding (CRIB) domain and a carboxyl terminal kinase domain [3] . PAKs are categorized into group I (PAK1, 2, and 3) and II (PAK4, 5, and 6) based on their amino acid sequences and functions [4] .…”

Section: Introductionmentioning

confidence: 99%

P21-activated kinase 5 plays essential roles in the proliferation and tumorigenicity of human hepatocellular carcinoma

Fang¹,

Jiang

et al. 2013

Acta Pharmacol Sin

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Aim: To investigate the roles of P21-activated kinase 5 (PAK5) in proliferation and tumorigenicity of human hepatocellular carcinoma (HCC). Methods: HCC and matched paraneoplastictis tissue samples were obtained from 30 patients. Human HCC cell lines SMMC7721, HepG2, Hep3B, SK-HEP-1, Huh-7, and liver cell line HL-7702 were examined. The expression of PAK5 gene was studied using real-time qPCR and Western blotting. Cell proliferation was quantified with the MTT assay. Cell cycle was analyzed with flow cytometry. The tumorigenicity of Lv-shRNA-transfected HepG2 cells was evaluated in BALB/cA nude mice. Results: The mRNA level of PAK5 was significantly higher in 25 out of 30 HCC samples compared to the matched paraneoplastic tissues. The HCC cell lines showed varying expression of PAK5 protein, and the highest level was found in the HepG2 cells. PAK5 gene silencing in HepG2 cells markedly reduced the cell proliferation and colony formation, and induced cell cycle arrest in the G 1 phase. Furthermore, PAK5 gene silencing suppressed the tumor formation in nude mice, and significantly decreased the expression of HCCrelated genes Cyclin D1 and beta-catenin. Conclusion: PAK5 may play essential roles in the initiation and progression of human HCC. Thus, it may be an effective therapeutic target or perhaps serve as a clinical diagnostic or prognostic marker in human HCC.

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Emerging from the Pak: the p21-activated protein kinase family

Cited by 287 publications

References 51 publications

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

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

Myo3A, One of Two Class III Myosin Genes Expressed in Vertebrate Retina, Is Localized to the Calycal Processes of Rod and Cone Photoreceptors and Is Expressed in the Sacculus

P21-activated kinase 5 plays essential roles in the proliferation and tumorigenicity of human hepatocellular carcinoma

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