Activated Cdc42-associated kinase Ack1 promotes prostate cancer progression via androgen receptor tyrosine phosphorylation

Mahajan, Nupam P.; Liu, Yuanbo; Majumder, Samarpan; Warren, Maria R.; Parker, Carol E.; Mohler, James L.; Earp, H. Shelton; Whang, Young E.

doi:10.1073/pnas.0700420104

Cited by 221 publications

(287 citation statements)

References 25 publications

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“…Similar findings were found at Y267 and Y363, which were phosphorylated by ACK1 tyrosine kinase, which was also increased in clinical samples of castration-recurrent CaP. [60] …”

Section: Androgen-receptor Immunostaining In Castration-recurrent Prosupporting

confidence: 75%

A role for the androgen-receptor in clinically localized and advanced prostate cancer

Mohler

2008

Best Practice & Research Clinical Endocrinology & Metab

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Earlier studies of androgen-receptor (AR) expression using frozen prostate tissue, and later studies using archived specimens, produced the consensus that ligand-stabilized AR is nuclear, AR expression is similar in benign epithelia and stroma, AR expression is greater in secretory epithelia than basal cells, and AR expression is more variable in prostate cancer (CaP) than in benign prostatic hyperplasia (BPH). Accurate measurement of AR expression remains technically challenging but necessary to evaluate the relevance of ARs to clinical CaP. Recent studies demonstrated that AR expression in epithelia and stroma may be prognostic in clinically localized CaP, and AR expression may play a role in racial differences in CaP mortality and predict response to androgen deprivation therapy. High levels of AR and AR-regulated gene expression indicate a central role for AR in growth regulation of castration-recurrent CaP. New treatments for the lethal phenotype of CaP require better understanding of AR transactivation during androgen deprivation therapy. Keywordsandrogen receptor; prostate cancer; quantitative video image analysis; immunohistochemistry Androgens are necessary for the development and growth of the prostate and for the development, growth and progression of prostate cancer (CaP). An American man is diagnosed with CaP every 3 minutes,[1] and the worldwide incidence of CaP is increasing an estimated 1.1% annually.[2] Despite increased use of digital rectal examination and serum prostatespecific antigen (PSA) measurement for early detection, approximately 30% of men treated with curative intent suffer CaP recurrence. These men, and those who present with locally advanced or metastatic CaP, can be palliated by androgen deprivation therapy (ADT), which causes regression of androgen-dependent CaP through programmed cell death.[3] Although there are many methods for medical and surgical ADT, the results of ADT remain unimproved since its discovery more than 60 years ago.[4] More than 80% of men with disseminated CaP demonstrate clinical or biochemical response that is associated with a mean life expectancy of approximately 3.5 years, in contrast to non-responders or untreated patients who live an average of 9 months. Regardless of the androgen responsiveness of incurable CaP, almost all patients succumb to castration-recurrent CaP because it responds poorly to all known therapies, and

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“…Similar findings were found at Y267 and Y363, which were phosphorylated by ACK1 tyrosine kinase, which was also increased in clinical samples of castration-recurrent CaP. [60] …”

Section: Androgen-receptor Immunostaining In Castration-recurrent Prosupporting

confidence: 75%

A role for the androgen-receptor in clinically localized and advanced prostate cancer

Mohler

2008

Best Practice & Research Clinical Endocrinology & Metab

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“…Other tyrosine kinases potently inhibited by bosutinib include the tumor suppressor EPHB4, FER, PTK2 (FAK), PYK2, SYK and TNK2, a nonreceptor protein tyrosine kinase whose overexpression in many human cancers is often associated with poor prognosis and knockdown of which leads to increased apoptosis in transformed cells. [21][22][23] In addition, several serine/ threonine kinases, for example, the NAK family members AAK1, BIKE and GAK, were identified. Interestingly, the MAPK super family was found to be a major target group of bosutinib.…”

Section: Resultsmentioning

confidence: 99%

Global target profile of the kinase inhibitor bosutinib in primary chronic myeloid leukemia cells

et al. 2008

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The detailed molecular mechanism of action of secondgeneration BCR-ABL tyrosine kinase inhibitors, including perturbed targets and pathways, should contribute to rationalized therapy in chronic myeloid leukemia (CML) or in other affected diseases. Here, we characterized the target profile of the dual SRC/ABL inhibitor bosutinib employing a two-tiered approach using chemical proteomics to identify natural binders in whole cell lysates of primary CML and K562 cells in parallel to in vitro kinase assays against a large recombinant kinase panel. The combined strategy resulted in a global survey of bosutinib targets comprised of over 45 novel tyrosine and serine/ threonine kinases. We have found clear differences in the target patterns of bosutinib in primary CML cells versus the K562 cell line. A comparison of bosutinib with dasatinib across the whole kinase panel revealed overlapping, but distinct, inhibition profiles. Common among those were the SRC, ABL and TEC family kinases. Bosutinib did not inhibit KIT or platelet-derived growth factor receptor, but prominently targeted the apoptosis-linked STE20 kinases. Although in vivo bosutinib is inactive against ABL T315I, we found this clinically important mutant to be enzymatically inhibited in the midnanomolar range. Finally, bosutinib is the first kinase inhibitor shown to target CAMK2G, recently implicated in myeloid leukemia cell proliferation.

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“…In androgen-depleted conditions, tyrosine kinase, non-receptor, 2 (TNK2 or ACK1), SRC, and erythroblastic leukemia viral oncogene homolog 2 [ERBB2 (HER-2/neu)] tyrosine kinase activity can restore AR function in prostate cancer cells (14)(15)(16)(17). Increased expression of the tyrosine kinase SRC and AR can synergistically drive frank carcinoma of the mouse prostate (18).…”

mentioning

confidence: 99%

Oncogene-specific activation of tyrosine kinase networks during prostate cancer progression

Drake

Graham²,

Stoyanova

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

144

145

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Dominant mutations or DNA amplification of tyrosine kinases are rare among the oncogenic alterations implicated in prostate cancer. We demonstrate that castration-resistant prostate cancer (CRPC) in men exhibits increased tyrosine phosphorylation, raising the question of whether enhanced tyrosine kinase activity is observed in prostate cancer in the absence of specific tyrosine kinase mutation or DNA amplification. We generated a mouse model of prostate cancer progression using commonly perturbed non-tyrosine kinase oncogenes and pathways and detected a significant up-regulation of tyrosine phosphorylation at the carcinoma stage. Phosphotyrosine peptide enrichment and quantitative mass spectrometry identified oncogene-specific tyrosine kinase signatures, including activation of EGFR, ephrin type-A receptor 2 (EPHA2), and JAK2. Kinase:substrate relationship analysis of the phosphopeptides also revealed ABL1 and SRC tyrosine kinase activation. The observation of elevated tyrosine kinase signaling in advanced prostate cancer and identification of specific tyrosine kinase pathways from genetically defined tumor models point to unique therapeutic approaches using tyrosine kinase inhibitors for advanced prostate cancer.AKT | androgen receptor | ERG | K-RAS | bioinformatics

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Activated Cdc42-associated kinase Ack1 promotes prostate cancer progression via androgen receptor tyrosine phosphorylation

Abstract: Ack1 tyrosine kinase ͉ signal transduction ͉ HER2 ͉ cross-talk

Cited by 221 publications

References 25 publications

A role for the androgen-receptor in clinically localized and advanced prostate cancer

A role for the androgen-receptor in clinically localized and advanced prostate cancer

Global target profile of the kinase inhibitor bosutinib in primary chronic myeloid leukemia cells

Oncogene-specific activation of tyrosine kinase networks during prostate cancer progression

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