| 1. |
- Chougule, Rohit A., et al.
(författare)
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Expression of GADS enhances FLT3-induced mitogenic signaling.
- 2016
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Ingår i: Oncotarget. - : Impact Journals, LLC. - 1949-2553. ; 7:12, s. 14112-14124
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Tidskriftsartikel (refereegranskat)abstract
- GADS is a member of a family of SH2 and SH3 domain-containing adaptors that functions in tyrosine kinase-mediated signaling cascades. Its expression is largely restricted to hematopoietic tissues and cell lines. Therefore, GADS is mainly involved in leukocyte-specific protein tyrosine kinase signaling. GADS is known to interact with tyrosine-phosphorylated SHC, BCR-ABL and KIT. The SH2 domain of GADS has a similar binding specificity to that of GRB2 but its SH3 domain displays a different binding specificity, and thus it is involved in other downstream signaling pathways than GRB2. In the present study, we examined the role of GADS in FLT3 signaling. FLT3 is a type III receptor tyrosine kinase, which is mutated in more than 30% of acute myeloid leukemia (AML) and the most common mutations is the internal tandem duplication (ITD) mutations. We observed that expression of GADS enhanced oncogenic FLT3-ITD-induced cell proliferation and colony formation in vitro. In a mouse xenograft model, GADS accelerated FLT3-ITD-dependent tumor formation. Furthermore, expression of GADS induced a transcriptional program leading to upregulation of MYC and mTORC1 target genes. GADS localizes to the cell membrane and strongly binds to ligand-stimulated wild-type FLT3 or is constitutively associated with the oncogenic mutant FLT3-ITD. We mapped the binding sites in FLT3 to pY955 and pY969 which overlaps with the GRB2 binding sites. Expression of GADS enhanced FLT3-mediated phosphorylation of AKT, ERK1/2, p38 and STAT5. Taken together, our data suggests that GADS is an important downstream component of FLT3 signaling and expression of GADS potentiates FLT3-mediated mitogenic signaling.
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| 2. |
- Moharram, Sausan A, et al.
(författare)
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Src-like adaptor protein 2 (SLAP2) binds to and inhibits FLT3 signaling
- 2016
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Ingår i: Oncotarget. - : Impact Journals, LLC. - 1949-2553. ; , s. 1-13
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Tidskriftsartikel (refereegranskat)abstract
- Fms-like tyrosine kinase (FLT3) is a frequently mutated oncogene in acute myeloid leukemia (AML). FLT3 inhibitors display promising results in a clinical setting, but patients relapse after short-term treatment due to the development of resistant disease. Therefore, a better understanding of FLT3 downstream signal transduction pathways will help to identify an alternative target for the treatment of AML patients carrying oncogenic FLT3. Activation of FLT3 results in phosphorylation of FLT3 on several tyrosine residues that recruit SH2 domain-containing signaling proteins. We screened a panel of SH2 domain-containing proteins and identified SLAP2 as a potent interacting partner of FLT3. We demonstrated that interaction occurs when FLT3 is activated, and also, an intact SH2 domain of SLAP2 is required for binding. SLAP2 binding sites in FLT3 mainly overlap with those of SRC. SLAP2 over expression in murine proB cells or myeloid cells inhibited oncogenic FLT3-ITD-mediated cell proliferation and colony formation in vitro, and tumor formation in vivo. Microarray analysis suggests that higher SLAP2 expression correlates with a gene signature similar to that of loss of oncogene function. Furthermore, FLT3-ITD positive AML patients with higher SLAP2 expression displayed better prognosis compared to those with lower expression of SLAP2. Expression of SLAP2 blocked FLT3 downstream signaling cascades including AKT, ERK, p38 and STAT5. Finally, SLAP2 accelerated FLT3 degradation through enhanced ubiquitination. Collectively, our data suggest that SLAP2 acts as a negative regulator of FLT3 signaling and therefore, modulation of SLAP2 expression levels may provide an alternative therapeutic approach for FLT3-ITD positive AML.
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| 3. |
- Kazi, Julhash U., et al.
(författare)
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FMS-Like Tyrosine Kinase-3
- 2016. - 2nd
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Ingår i: Encyclopedia of Signaling Molecules. - New York, NY : Springer New York. - 9781461464389 ; , s. 1-4
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Bokkapitel (övrigt vetenskapligt/konstnärligt)
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| 4. |
- Moharram, Sausan A., et al.
(författare)
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Src-Like Adapter Protein 2 (SLAP2)
- 2016
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Ingår i: Encyclopedia of Signaling Molecules. - New York, NY : Springer New York. - 9781461464389 - 9781461464389 ; 2, s. 1-4
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Bokkapitel (övrigt vetenskapligt/konstnärligt)
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| 5. |
- Moharram, Sausan A., et al.
(författare)
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Src-Like Adapter Protein (SLAP)
- 2016
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Ingår i: Encyclopedia of Signaling Molecules. - New York, NY : Springer New York. - 9781461464389 - 9781461464389 ; , s. 1-4
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Bokkapitel (övrigt vetenskapligt/konstnärligt)
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