The Src tyrosine kinase Hck is required for Tel-Abl- but not for Tel-Jak2-induced cell transformation

Pecquet, Christian; Nyga, Rémy; Penard-Lacronique, Virginie; Smithgall, Thomas E.; Murakami, Hisashi; Régnier, Aline; Lassoued, Kaı̈ss; Gouilleux, Fabrice

doi:10.1038/sj.onc.1209949

Cited by 24 publications

(21 citation statements)

References 40 publications

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“…20 Recently, constitutive activation of STAT proteins has been observed in several malignant neoplasms. [21][22][23] Like STAT3, STAT5 has been shown to actively participate in tumor development and progression. [24][25][26][27] However, the precise role of STAT5 signaling in human CRC progression has not been characterized.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of STAT5 induces G1 cell cycle arrest and reduces tumor cell invasion in human colorectal cancer cells

Xiong

Liang

et al. 2009

Laboratory Investigation

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Abnormalities in the signal transducer and activator of transcription (STAT) pathway are involved in the oncogenesis of several cancers. However, the mechanism by which dysregulated STAT5 signaling contributes to the progression of human colorectal cancer (CRC) has not been elucidated. To investigate the role of STAT5 in CRC progression, we depleted STAT5 with a small interfering RNA (siRNA). Our results demonstrate that STAT5 is involved in CRC cell growth, cell cycle progression, invasion and migration through regulation of gene expression, such as Bcl-2, p16 ink4a , p21 waf1/cip1 , p27 kip1 , E-cadherin, the focal adhesion kinase (FAK), vascular endothelial growth factor (VEGF) and matrix metalloproteinases. In addition, immunohistochemical staining reveals upregulation of STAT5 during CRC tumorigenesis. Moreover, phospho-STAT5 (pSTAT5) is predominantly localized in the cytoplasm of adenomas cells and colon adenocarcinoma cells, but primarily presented in the nucleus of normal colonic epithelium cells. Thus, pSTAT5 protein is shuttled from the nucleus to the cytoplasm in the oncogenesis of CRC, suggesting that activated STAT5 may also have cytoplasmic functions. In support of this hypothesis, we found that STAT5 formed a complex with p44/42 MAPK and SAPK/JNK in CRC cells, suggesting cross talk between STAT5 signaling and the MAPK pathway in the development of human CRC. Our findings illustrate the biological significance of STAT5 signaling in CRC progression, and provide novel evidence that intervention in STAT5 signaling may have potential therapeutic value in the prevention of human colorectal cancer.

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Section: Discussionmentioning

confidence: 99%

Inhibition of STAT5 induces G1 cell cycle arrest and reduces tumor cell invasion in human colorectal cancer cells

Xiong

Liang

et al. 2009

Laboratory Investigation

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“…In vitro studies demonstrated that both aberrations lead to constitutive activation of the nonreceptor tyrosine kinase ABL1 with similar downstream effects associated to cellular growth, survival, growth factor independence and transforming capacity (Okuda et al, 1996;Malinge et al, 2006;Pecquet et al, 2007). However, differences between the two fusions have been described, for example, in the substrate preferences (Voss et al, 2000).…”

Section: Introductionmentioning

confidence: 95%

Acute leukemias with ETV6/ABL1 (TEL/ABL) fusion: Poor prognosis and prenatal origin

Zuna

Žaliová

Mužíková

et al. 2010

Genes Chromosomes & Cancer

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The ETV6/ABL1 (TEL/ABL) fusion gene is a rare aberration in malignant disorders. Only 19 cases of ETV6/ABL1-positive hematological malignancy have been published, diagnosed with chronic myeloid leukemia, other types of chronic myeloproliferative neoplasm, acute myeloid leukemia or acute lymphoblastic leukemia (ALL). This study reports three new cases (aged 8 months, 5 years, and 33 years) of ALL with the ETV6/ABL1 fusion found by screening 392 newly diagnosed ALL patients (335 children and 57 adults). A thorough review of the literature and an analysis of all published data, including the three new cases, suggest poor prognosis of ETV6/ABL1-positive acute leukemias. The course of the disease in the two pediatric patients is characterized by minimal residual disease monitoring, using quantification of both the ETV6/ABL1 transcript and immunoreceptor gene rearrangements. Eosinophilia could not be confirmed as a hallmark of the ETV6/ABL1-positive disease. Studies of neonatal blood spots demonstrated that, in the child diagnosed at five years, the ETV6/ABL1 fusion initiating the ALL originated prenatally.

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“…We focused our efforts on PI3K/AKT, mitogen-activated protein kinase (MAPK), and BTK signaling pathways given their established importance in WM survival, as well as previous work implicating HCK as an upstream regulator for their signaling. [21][22][23][24] Transduction of HCK in IL-6-producing BCWM.1 and MWCL-1 cells led to higher HCK protein levels by western blot analysis and detection of activated HCK (Tyr 411 ) by Phosflow analysis (Figure 5A-B). Transduction of HCK in BCWM.1 and MWCL-1 cells also triggered PI3K/AKT (pPIK3R2 and pAKT), MAPK (pPLCg1 and pERK1/2), and BTK (pBTK and pPLCg2) signaling ( Figure 5B), whereas knockdown of HCK in BCWM.1 and MWCL-1 cells showed a reciprocal pattern, with diminished PI3K/AKT, MAPK, and BTK signaling ( Figure 5C).…”

Section: Hck Triggers Pro-survival Signaling In Myd88-mutated Wm Cellsmentioning

confidence: 99%

HCK is a survival determinant transactivated by mutated MYD88, and a direct target of ibrutinib

Yang

Buhrlage

et al. 2016

Blood

101

115

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Key Points• HCK transcription and activation is triggered by mutated MYD88, and is an important determinant of pro-survival signaling.• HCK is also a target of ibrutinib, and inhibition of its kinase activity triggers apoptosis in mutated MYD88 cells.Activating mutations in MYD88 are present in ∼95% of patients with Waldenström macroglobulinemia (WM), as well as other B-cell malignancies including activated B-cell (ABC) diffuse large B-cell lymphoma (DLBCL). In WM, mutated MYD88 triggers activation of Bruton tyrosine kinase (BTK). Ibrutinib, a pleiotropic kinase inhibitor that targets BTK, is highly active in patients with mutated MYD88. We observed that mutated MYD88 WM and ABC DLBCL cell lines, as well as primary WM cells show enhanced hematopoietic cell kinase (HCK) transcription and activation, and that HCK is activated by interleukin 6 (IL-6). Over-expression of mutated MYD88 triggers HCK and IL-6 transcription, whereas knockdown of HCK reduced survival and attenuated BTK, phosphoinositide 3-kinase/ AKT, and mitogen-activated protein kinase/extracellular signal-regulated kinase signaling in mutated MYD88 WM and/or ABC DLBCL cells. Ibrutinib and the more potent HCK inhibitor A419259, blocked HCK activation and induced apoptosis in mutated MYD88 WM and ABC DLBCL cells. Docking and pull-down studies confirmed that HCK was a target of ibrutinib. Ibrutinib and A419259 also blocked adenosine triphosphate binding to HCK, whereas transduction of mutated MYD88 expressing WM cells with a mutated HCK gatekeeper greatly increased the half maximal effective concentration for ibrutinib and A419259. The findings support that HCK expression and activation is triggered by mutated MYD88, supports the growth and survival of mutated MYD88 WM and ABC DLBCL cells, and is a direct target of ibrutinib. HCK represents a novel target for therapeutic development in MYD88-mutated WM and ABC DLBCL, and possibly other diseases driven by mutated MYD88. (Blood. 2016;127(25):3237-3252)

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The Src tyrosine kinase Hck is required for Tel-Abl- but not for Tel-Jak2-induced cell transformation

Cited by 24 publications

References 40 publications

Inhibition of STAT5 induces G1 cell cycle arrest and reduces tumor cell invasion in human colorectal cancer cells

Inhibition of STAT5 induces G1 cell cycle arrest and reduces tumor cell invasion in human colorectal cancer cells

Acute leukemias with ETV6/ABL1 (TEL/ABL) fusion: Poor prognosis and prenatal origin

HCK is a survival determinant transactivated by mutated MYD88, and a direct target of ibrutinib

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