Requirement of Activated Cdc42-Associated Kinase for Survival of v-Ras-Transformed Mammalian Cells

Nur‐E‐Kamal, Alam; Zhang, Ailing; Keenan, Susan M.; Wang, Xin I.; Seraj, Jabed; Satoh, Takaya; Meiners, Scott J.; Welsh, William J.

doi:10.1158/1541-7786.mcr-04-0152

Cited by 24 publications

(10 citation statements)

References 55 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…To date, there is no direct connection between the two proteins, with exception to the publication by Nur et al [16]. Their work and ours suggested ACK1 is an important pro-oncogenic factor downstream of constitutive active RAS, probably also mediating EMT.…”

Section: Discussionmentioning

confidence: 53%

“…In melanoma cell lines, ACK1 is activated in response to integrin signaling, resulting in cell spreading [15]. In vivo , ACK1 over-expressing cells resulted in aggressive metastatic tumors [10,12] while in vitro silencing of the ACK1 gene in RAS-transformed NIH3T3 cells increased apoptosis [16]. Recently, we have also shown that silencing of ACK1 results in reduced ERK and AKT phosphorylation and interestingly, EMT reversion [17].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Bosutinib inhibits migration and invasion via ack1 in kras mutant non-small cell lung cancer

et al. 2014

View full text Add to dashboard Cite

The advent of effective targeted therapeutics has led to increasing emphasis on precise biomarkers for accurate patient stratification. Here, we describe the role of ACK1, a non-receptor tyrosine kinase in abrogating migration and invasion in KRAS mutant lung adenocarcinoma. Bosutinib, which inhibits ACK1 at 2.7 nM IC50, was found to inhibit cell migration and invasion but not viability in a panel of non-small cell lung cancer (NSCLC) cell lines. Knockdown of ACK1 abrogated bosutinib-induced inhibition of cell migration and invasion specifically in KRAS mutant cells. This finding was further confirmed in an in vivo zebrafish metastatic model. Tissue microarray data on 210 Singaporean lung adenocarcinomas indicate that cytoplasmic ACK1 was significantly over-expressed relative to paired adjacent non-tumor tissue. Interestingly, ACK1 expression in “normal” tissue adjacent to tumour, but not tumour, was independently associated with poor overall and relapse-free survival. In conclusion, inhibition of ACK1 with bosutinib attenuates migration and invasion in the context of KRAS mutant NSCLC and may fulfil a therapeutic niche through combinatorial treatment approaches.

show abstract

Section: Discussionmentioning

confidence: 53%

Section: Introductionmentioning

confidence: 99%

Bosutinib inhibits migration and invasion via ack1 in kras mutant non-small cell lung cancer

et al. 2014

View full text Add to dashboard Cite

show abstract

“…21 Furthermore, ACK1 has been reported to be required for survival of v-H-Ras-transformed mammalian cells. 28 Overall, it seems likely that inhibition of ACK1 by GNF-7 contributes to the suppression of AKT signaling.…”

Section: Discussionmentioning

confidence: 99%

Identification of novel therapeutic targets in acute leukemias with NRAS mutations using a pharmacologic approach

Nonami

Sattler

Weisberg

et al. 2015

Blood

View full text Add to dashboard Cite

Oncogenic forms of NRAS are frequently associated with hematologic malignancies and other cancers, making them important therapeutic targets. Inhibition of individual downstream effector molecules (eg, RAF kinase) have been complicated by the rapid development of resistance or activation of bypass pathways. For the purpose of identifying novel targets in NRAS-transformed cells, we performed a chemical screen using mutant NRAS transformed Ba/F3 cells to identify compounds with selective cytotoxicity. One of the compounds identified, GNF-7, potently and selectively inhibited NRAS-dependent cells in preclinical models of acute myelogenous leukemia and acute lymphoblastic leukemia. Mechanistic analysis revealed that its effects were mediated in part through combined inhibition of ACK1/AKT and of mitogen-activated protein kinase kinase kinase kinase 2 (germinal center kinase). Similar to genetic synthetic lethal approaches, these results suggest that small molecule screens can be used to identity novel therapeutic targets in cells addicted to RAS oncogenes.

show abstract

“…For example, Ack1's role as a potential downstream effector of GTP-bound Cdc42 on cytoskeletal or integrin dynamics is a possibility, as are alterations in gene expression. Recently, it has been shown that Ras transformants, but not normal cells, are highly reliant on the Ack1 kinase for both survival and growth, suggesting that Ack1 plays a role in transducing Ras signals for transformation of mammalian cells (54). The fact that Ack1 can significantly enhance prostate tumorigenesis in vivo indicates that both upstream and downstream Ack1 signaling pathways may provide potential targets for drug discovery in prostate cancer and paves the way for new therapeutic strategies in advanced prostate cancer.…”

Section: Discussionmentioning

confidence: 99%

Activated Tyrosine Kinase Ack1 Promotes Prostate Tumorigenesis: Role of Ack1 in Polyubiquitination of Tumor Suppressor Wwox

et al. 2005

View full text Add to dashboard Cite

Aberrant activation of tyrosine kinases is linked causally to human cancers. Activated Cdc42-associated kinase (Ack1), an intracellular tyrosine kinase, has primarily been studied for its signaling properties but has not been linked to specific pathologic conditions. Herein, we report that expression of activated Ack1 in LNCaP cells, while minimally increasing growth in culture, enhanced anchorage-independent growth in vitro and dramatically accelerated tumorigenesis in nude mice. Molecular chaperone heat shock protein 90B (Hsp90B)-bound Ack1 and treatment of cells with geldanamycin, a Hsp90 inhibitor, inhibited Ack1 kinase activity and suppressed tumorigenesis. Further, we identify the tumor suppressor WW domain containing oxidoreductase (Wwox) as an Ack1-interacting protein. Activated Ack1 tyrosine phosphorylated Wwox, leading to rapid dissociation of the Ack1-Wwox complex and concomitant Wwox polyubiquitination followed by degradation. Tyrosine phosphorylation of Wwox was critical for its degradation, as splice variant Wwox#5-8 that was not phosphorylated by Ack1 failed to undergo polyubiquitination and degradation. It has been reported that phosphorylation of Wwox at Tyr 33 stimulated its proapoptotic activity. We observed that Y33F Wwox mutant was still tyrosine phosphorylated and polyubiquitinated by Ack1 action. Site-directed mutagenesis revealed that activated Ack1 primarily phosphorylated Wwox at Tyr 287 , suggesting that phosphorylation of distinct tyrosine residues activate or degrade Wwox. Primary androgen-independent prostate tumors but not benign prostate showed increased tyrosinephosphorylated Ack1 and decreased Wwox. Taken together, these data indicate that Ack1 stimulated prostate tumorigenesis in part by negatively regulating the proapoptotic tumor suppressor, Wwox. Further, these findings suggest that Ack1 could be a novel therapeutic target for prostate cancer. (Cancer Res 2005; 65(22): 10514-23)

show abstract

Requirement of Activated Cdc42-Associated Kinase for Survival of v-Ras-Transformed Mammalian Cells

Cited by 24 publications

References 55 publications

Bosutinib inhibits migration and invasion via ack1 in kras mutant non-small cell lung cancer

Bosutinib inhibits migration and invasion via ack1 in kras mutant non-small cell lung cancer

Identification of novel therapeutic targets in acute leukemias with NRAS mutations using a pharmacologic approach

Activated Tyrosine Kinase Ack1 Promotes Prostate Tumorigenesis: Role of Ack1 in Polyubiquitination of Tumor Suppressor Wwox

Contact Info

Product

Resources

About