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Oncotarget. 2016 Mar 22;7(12):14112-24. doi: 10.18632/oncotarget.7415.

Expression of GADS enhances FLT3-induced mitogenic signaling.

Author information

1
Division of Translational Cancer Research, Department of Laboratory Medicine, Lund University, Lund, Sweden.
2
Lund Stem Cell Center, Department of Laboratory Medicine, Lund University, Lund, Sweden.
3
Lund University Cancer Center, Medicon Village, Lund, Sweden.

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.

KEYWORDS:

AML; FLT3-ITD; GRAP2; RTK; STAT5

PMID:
26895103
PMCID:
PMC4924701
DOI:
10.18632/oncotarget.7415
[Indexed for MEDLINE]
Free PMC Article

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