| 1. |
- Agarwal, Shruti, et al.
(författare)
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Phosphorylation of the activation loop tyrosine 823 in c-Kit is crucial for cell survival and proliferation.
- 2013
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Ingår i: Journal of Biological Chemistry. - 1083-351X. ; 288:31, s. 22460-22468
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Tidskriftsartikel (refereegranskat)abstract
- The receptor tyrosine kinase c-Kit, also known as the stem cell factor receptor, plays a key role in several developmental processes. Activating mutations in c-Kit lead to alteration of these cellular processes and have been implicated in many human cancers such as gastrointestinal stromal tumors (GISTs), acute myeloid leukemia (AML), testicular seminomas and mastocytosis. Regulation of the catalytic activity of several kinases is known to be governed by phosphorylation of tyrosine residues in the activation loop of the kinase domain. However, in the case of c-Kit phosphorylation of Y823 has been demonstrated to be a late event that is not required for kinase activation. However, since phosphorylation of Y823 is a ligand-activated event, we sought to investigate the functional consequences of Y823 phosphorylation. By using a tyrosine to phenylalanine mutant of tyrosine 823 we investigated the impact of Y823 on c-Kit signaling. We here demonstrate that Y823 is crucial for cell survival and proliferation and mutation of Y823 to phenylalanine leads to decreased sustained phosphorylation and ubiquitination of c-Kit as compared to the wild-type receptor. Furthermore, the mutated receptor was upon ligand-stimulation quickly internalized and degraded. Phosphorylation of the E3 ubiquitin ligase, Cbl was transient followed by a substantial reduction in phosphorylation of downstream signaling molecules such as Akt, Erk, Shc and Gab2. Thus, we propose that activation loop tyrosine 823 is crucial for activation of both the MAPK and PI3K pathways and that its disruption leads to a destabilization of the c-Kit receptor and decreased survival of cells.
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| 2. |
- Kabir, Nuzhat N., et al.
(författare)
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Deregulation of protein phosphatase expression in acute myeloid leukemia
- 2013
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Ingår i: Medical Oncology. - : Springer Science and Business Media LLC. - 1559-131X .- 1357-0560. ; 30:2
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Tidskriftsartikel (refereegranskat)abstract
- Acute myeloid leukemia (AML) is a highly malignant disease of myeloid cell line. AML is the most frequent adult leukemia with inadequate treatment possibility. The protein phosphatases are critical regulators of cell signaling, and deregulation of protein phosphatases always contribute to cell transformation. Although many studies established a relationship between protein phosphatases and leukemia, little is known about the role of this group of proteins in AML. To address this issue, we initially identified the complete catalog of human protein phosphatase genes and used this catalog to study deregulation of protein phosphatases in AML. Using mRNA expression data of AML patients, we show that 11 protein phosphatases are deregulated in AML within 174 protein phosphatases. The GO enrichment study suggests that these genes are involved in multiple biological processes other than protein de-phosphorylation. Expression of DUSP10, PTPRC, and PTPRE was significantly higher than average expression in AML, and a linear combination of DUSP10, MTMR11, PTPN4, and PTPRE expressions provides important information about disease subtypes. Our results provide an overview of protein phosphatase deregulation in AML.
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| 3. |
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| 4. |
- Kabir, Nuzhat N., et al.
(författare)
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Grb10 is a dual regulator of receptor tyrosine kinase signaling
- 2014
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Ingår i: Molecular Biology Reports. - : Springer Science and Business Media LLC. - 0301-4851 .- 1573-4978. ; 41:4, s. 1985-1992
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Forskningsöversikt (refereegranskat)abstract
- The adaptor protein Grb10 is a close homolog of Grb7 and Grb14. These proteins are characterized by an N-terminal proline-rich region, a Ras–GTPase binding domain, a PH domain, an SH2 domain and a BPS domain in between the PH and SH2 domains. Human Grb10 gene encodes three splice variants. These variants show differences in functionality. Grb10 associates with multiple proteins including tyrosine kinases in a tyrosine phosphorylation dependent or independent manner. Association with multiple proteins allows Grb10 to regulate different signaling pathways resulting in different biological consequences.
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| 5. |
- Kabir, Nuzhat N., et al.
(författare)
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Keratin 19 expression correlates with poor prognosis in breast cancer
- 2014
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Ingår i: Molecular Biology Reports. - : Springer Science and Business Media LLC. - 0301-4851 .- 1573-4978. ; 41:12, s. 7729-7735
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Tidskriftsartikel (refereegranskat)abstract
- Breast cancer expression profiling has been used for determining biomarkers. Using gene expression profiles of 2,400 patients we identified keratin 19 (KRT19) as a highly deregulated gene in breast cancer. KRT19 expression is independent of patient race but correlates with disease grade, and ER, PR or HER2 expression. Expression of TPD52, GATA3 and KRT18 was increased in KRT19 expressing patients. Furthermore, KRT19 expression was associated with ER up-regulation and Luminal B gene signatures, as well as a constitutive RAF1 signaling pathway. Finally, KRT19 expression correlated with poor overall survival. Taken together, our results suggest that KRT19 expression can be used as a prognostic marker.
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| 7. |
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| 8. |
- Kabir, Nuzhat N., et al.
(författare)
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SOCS6 is a selective suppressor of receptor tyrosine kinase signaling
- 2014
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Ingår i: Tumor Biology. - : Springer Science and Business Media LLC. - 1423-0380 .- 1010-4283. ; 35:11, s. 10581-10589
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Forskningsöversikt (refereegranskat)abstract
- The suppressors of cytokine signaling (SOCS) are well-known negative regulators of cytokine receptor signaling. SOCS6 is one of eight members of the SOCS family of proteins. Similar to other SOCS proteins, SOCS6 consists of an uncharacterized extended N-terminal region followed by an SH2 domain and a SOCS box. Unlike other SOCS proteins, SOCS6 is mainly involved in negative regulation of receptor tyrosine kinase signaling. SOCS6 is widely expressed in many tissues and is found to be downregulated in many cancers including colorectal cancer, gastric cancer, lung cancer, ovarian cancer, stomach cancer, thyroid cancer, hepatocellular carcinoma, and pancreatic cancer. SOCS6 is involved in negative regulation of receptor signaling by increasing degradation mediated by ubiquitination of receptors or substrate proteins and induces apoptosis by targeting mitochondrial proteins. Therefore, SOCS6 turns out as an important regulator of survival signaling and its activity is required for controlling receptor tyrosine kinase signaling.
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| 9. |
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| 10. |
- Kazi, Julhash U., et al.
(författare)
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FLT3 signals via the adapter protein Grb10 and overexpression of Grb10 leads to aberrant cell proliferation in acute myeloid leukemia.
- 2013
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Ingår i: Molecular Oncology. - : Wiley. - 1574-7891. ; 7:3, s. 402-418
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Tidskriftsartikel (refereegranskat)abstract
- The adaptor protein Grb10 plays important roles in mitogenic signaling. However, its roles in acute myeloid leukemia (AML) are predominantly unknown. Here we describe the role of Grb10 in FLT3-ITD-mediated AML. We observed that Grb10 physically associates with FLT3 in response to FLT3-ligand (FL) stimulation through FLT3 phospho-tyrosine 572 and 793 residues and constitutively associates with oncogenic FLT3-ITD. Furthermore endogenous Grb10-FLT3 association was observed in OCI-AML-5 cells. Grb10 expression did not alter FLT3 receptor activation or stability in Ba/F3-FLT3 cells. However, expression of Grb10 enhanced FL-induced Akt phosphorylation without affecting Erk or p38 phosphorylation in Ba/F3-FLT3-WT and Ba/F3-FLT3-ITD. Selective Grb10 depletion reduced Akt phosphorylation in Ba/F3-FLT3-WT and OCI-AML-5 cells. Grb10 transduces signal from FLT3 by direct interaction with p85 and Ba/F3-FLT3-ITD cells expressing Grb10 exhibits higher STAT5 activation. Grb10 regulates the cell cycle by increasing cell population in S-phase. Expression of Grb10 furthermore resulted in an increased proliferation and survival of Ba/F3-FLT3-ITD cells as well as increased colony formation in semisolid culture. Grb10 expression was significantly increased in AML patients compared to healthy controls and was also elevated in patients carrying FLT3-ITD mutants. The elevated Grb10 expression partially correlated to relapse as well as to poor prognosis. These results suggest that Grb10 binds to both normal and oncogenic FLT3 and induces PI3K-Akt and STAT5 signaling pathways resulting in an enhanced proliferation, survival and colony formation of hematopoietic cells.
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