Src-Like Adaptor Protein (SLAP) Binds to the Receptor Tyrosine Kinase Flt3 and Modulates Receptor Stability and Downstream Signaling.
(2012) In PLoS ONE 7(12).- Abstract
- Fms-like tyrosine kinase 3 (Flt3) is an important growth factor receptor in hematopoiesis. Gain-of-function mutations of the receptor contribute to the transformation of acute myeloid leukemia (AML). Src-like adaptor protein (SLAP) is an interaction partner of the E3 ubiquitin ligase Cbl that can regulate receptor tyrosine kinases-mediated signal transduction. In this study, we analyzed the role of SLAP in signal transduction downstream of the type III receptor tyrosine kinase Flt3. The results show that upon ligand stimulation SLAP stably associates with Flt3 through multiple phosphotyrosine residues in Flt3. SLAP constitutively interacts with oncogenic Flt3-ITD and co-localizes with Flt3 near the cell membrane. This association initiates... (More)
- Fms-like tyrosine kinase 3 (Flt3) is an important growth factor receptor in hematopoiesis. Gain-of-function mutations of the receptor contribute to the transformation of acute myeloid leukemia (AML). Src-like adaptor protein (SLAP) is an interaction partner of the E3 ubiquitin ligase Cbl that can regulate receptor tyrosine kinases-mediated signal transduction. In this study, we analyzed the role of SLAP in signal transduction downstream of the type III receptor tyrosine kinase Flt3. The results show that upon ligand stimulation SLAP stably associates with Flt3 through multiple phosphotyrosine residues in Flt3. SLAP constitutively interacts with oncogenic Flt3-ITD and co-localizes with Flt3 near the cell membrane. This association initiates Cbl-dependent receptor ubiquitination and degradation. Depletion of SLAP expression by shRNA in Flt3-transfected Ba/F3 cells resulted in a weaker activation of FL-induced PI3K-Akt and MAPK signaling. Meta-analysis of microarray data from patient samples suggests that SLAP mRNA is differentially expressed in different cancers and its expression was significantly increased in patients carrying the Flt3-ITD mutation. Thus, our data suggest a novel role of SLAP in different cancers and in modulation of receptor tyrosine kinase signaling apart from its conventional role in regulation of receptor stability. (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/3438908
- author
- Kazi, Julhash U. LU and Rönnstrand, Lars LU
- organization
- publishing date
- 2012
- type
- Contribution to journal
- publication status
- published
- subject
- in
- PLoS ONE
- volume
- 7
- issue
- 12
- article number
- e53509
- publisher
- Public Library of Science (PLoS)
- external identifiers
-
- wos:000313872600105
- pmid:23300935
- scopus:84871794409
- pmid:23300935
- ISSN
- 1932-6203
- DOI
- 10.1371/journal.pone.0053509
- language
- English
- LU publication?
- yes
- additional info
- The information about affiliations in this record was updated in December 2015. The record was previously connected to the following departments: Experimental Clinical Chemistry (013016010)
- id
- 49a034f1-cb54-4a83-afcb-ec0af49f9f1a (old id 3438908)
- alternative location
- http://www.ncbi.nlm.nih.gov/pubmed/23300935?dopt=Abstract
- date added to LUP
- 2016-04-01 13:49:36
- date last changed
- 2022-03-21 20:42:34
@article{49a034f1-cb54-4a83-afcb-ec0af49f9f1a, abstract = {{Fms-like tyrosine kinase 3 (Flt3) is an important growth factor receptor in hematopoiesis. Gain-of-function mutations of the receptor contribute to the transformation of acute myeloid leukemia (AML). Src-like adaptor protein (SLAP) is an interaction partner of the E3 ubiquitin ligase Cbl that can regulate receptor tyrosine kinases-mediated signal transduction. In this study, we analyzed the role of SLAP in signal transduction downstream of the type III receptor tyrosine kinase Flt3. The results show that upon ligand stimulation SLAP stably associates with Flt3 through multiple phosphotyrosine residues in Flt3. SLAP constitutively interacts with oncogenic Flt3-ITD and co-localizes with Flt3 near the cell membrane. This association initiates Cbl-dependent receptor ubiquitination and degradation. Depletion of SLAP expression by shRNA in Flt3-transfected Ba/F3 cells resulted in a weaker activation of FL-induced PI3K-Akt and MAPK signaling. Meta-analysis of microarray data from patient samples suggests that SLAP mRNA is differentially expressed in different cancers and its expression was significantly increased in patients carrying the Flt3-ITD mutation. Thus, our data suggest a novel role of SLAP in different cancers and in modulation of receptor tyrosine kinase signaling apart from its conventional role in regulation of receptor stability.}}, author = {{Kazi, Julhash U. and Rönnstrand, Lars}}, issn = {{1932-6203}}, language = {{eng}}, number = {{12}}, publisher = {{Public Library of Science (PLoS)}}, series = {{PLoS ONE}}, title = {{Src-Like Adaptor Protein (SLAP) Binds to the Receptor Tyrosine Kinase Flt3 and Modulates Receptor Stability and Downstream Signaling.}}, url = {{https://lup.lub.lu.se/search/files/3613288/3910446.pdf}}, doi = {{10.1371/journal.pone.0053509}}, volume = {{7}}, year = {{2012}}, }