Expression of GADS enhances FLT3-induced mitogenic signaling.
(2016) In Oncotarget 7(12). p.14112-14124- 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... (More)
- 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. (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/8825022
- author
- Chougule, Rohit A. LU ; Cordero, Eugenia LU ; Moharram, Sausan A. LU ; Pietras, Kristian LU ; Rönnstrand, Lars LU and Kazi, Julhash U. LU
- organization
- publishing date
- 2016-02-15
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Oncotarget
- volume
- 7
- issue
- 12
- pages
- 14112 - 14124
- publisher
- Impact Journals
- external identifiers
-
- pmid:26895103
- scopus:84971596963
- pmid:26895103
- ISSN
- 1949-2553
- DOI
- 10.18632/oncotarget.7415
- language
- English
- LU publication?
- yes
- id
- bf8a216a-2b46-4e14-a9fa-66d4d6552e10 (old id 8825022)
- alternative location
- http://www.ncbi.nlm.nih.gov/pubmed/26895103?dopt=Abstract
- date added to LUP
- 2016-04-04 09:25:50
- date last changed
- 2022-08-23 07:05:06
@article{bf8a216a-2b46-4e14-a9fa-66d4d6552e10, 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.}}, author = {{Chougule, Rohit A. and Cordero, Eugenia and Moharram, Sausan A. and Pietras, Kristian and Rönnstrand, Lars and Kazi, Julhash U.}}, issn = {{1949-2553}}, language = {{eng}}, month = {{02}}, number = {{12}}, pages = {{14112--14124}}, publisher = {{Impact Journals}}, series = {{Oncotarget}}, title = {{Expression of GADS enhances FLT3-induced mitogenic signaling.}}, url = {{http://dx.doi.org/10.18632/oncotarget.7415}}, doi = {{10.18632/oncotarget.7415}}, volume = {{7}}, year = {{2016}}, }