Phosphatidylinositol 3 kinase contributes to the transformation of hematopoietic cells by the D816V c-Kit mutant
(2001) In Blood 98(5). p.1365-1373- Abstract
- Stem cell factor (SCF) binds the receptor tyrosine kinase c-Kit and is critical for normal hematopoiesis. Substitution of valine for aspartic acid 816 (D816V) constitutively actives human c-Kit, and this mutation is found in patients with mastocytosis, leukemia, and germ cell tumors. Immortalized murine progenitor cells (MIHCs) transduced with wild-type c-Kit proliferate in response to SCF, whereas cells expressing D816V c-Kit (MIHC-D816V) are factor-independent and tumorigenic. However, the mechanisms mediating transformation by D816V c-Kit are unknown. The objective of this study was to identify signaling components that contribute to D816V c-Kit-mediated transformation. SCF stimulates association of p85PI3K with phosphorylated tyrosine... (More)
- Stem cell factor (SCF) binds the receptor tyrosine kinase c-Kit and is critical for normal hematopoiesis. Substitution of valine for aspartic acid 816 (D816V) constitutively actives human c-Kit, and this mutation is found in patients with mastocytosis, leukemia, and germ cell tumors. Immortalized murine progenitor cells (MIHCs) transduced with wild-type c-Kit proliferate in response to SCF, whereas cells expressing D816V c-Kit (MIHC-D816V) are factor-independent and tumorigenic. However, the mechanisms mediating transformation by D816V c-Kit are unknown. The objective of this study was to identify signaling components that contribute to D816V c-Kit-mediated transformation. SCF stimulates association of p85PI3K with phosphorylated tyrosine 721 of wild-type c-Kit. Phosphatidylinositol 3 kinase (PI3K) subsequently contributes to the activation of Akt and Jnks. In contrast, these studies demonstrated that the D816V c-Kit mutant was constitutively associated with phosphorylated p85PI3K, and, downstream of PI3K, Jnk 1 and Jnk 2 were activated but Akt was not. Interestingly, Erks 1 and 2 were not constitutively activated by D816V c-Kit. Thus, D816V c-Kit maintains the activity of PI3K but not of all signaling pathways activated by wild-type c-Kit. Further, all pathways downstream of PI3K are not constitutively active in MIHC-D816V cells. Studies with a PI3K inhibitor and D816V/Y721F c-Kit, a mutant incapable of recruiting PI3K, indicate that constitutive activation of PI3K through direct recruitment by D816V c-Kit plays a role in factor-independent growth of MIHC and is critical for tumorigenicity. (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/1782460
- author
- Chian, R ; Young, S ; Danilkovitch-Miagkova, A ; Rönnstrand, Lars LU ; Ferrao, P ; Ashman, L and Linnekin, D
- publishing date
- 2001
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Blood
- volume
- 98
- issue
- 5
- pages
- 1365 - 1373
- publisher
- American Society of Hematology
- external identifiers
-
- scopus:0035469886
- ISSN
- 1528-0020
- language
- English
- LU publication?
- no
- 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
- 18de45e7-a729-40fa-bfda-1b0c4b745fdd (old id 1782460)
- alternative location
- http://www.ncbi.nlm.nih.gov/pubmed/11520784
- http://bloodjournal.hematologylibrary.org/content/98/5/1365.long
- date added to LUP
- 2016-04-04 08:56:37
- date last changed
- 2022-04-15 21:28:53
@article{18de45e7-a729-40fa-bfda-1b0c4b745fdd, abstract = {{Stem cell factor (SCF) binds the receptor tyrosine kinase c-Kit and is critical for normal hematopoiesis. Substitution of valine for aspartic acid 816 (D816V) constitutively actives human c-Kit, and this mutation is found in patients with mastocytosis, leukemia, and germ cell tumors. Immortalized murine progenitor cells (MIHCs) transduced with wild-type c-Kit proliferate in response to SCF, whereas cells expressing D816V c-Kit (MIHC-D816V) are factor-independent and tumorigenic. However, the mechanisms mediating transformation by D816V c-Kit are unknown. The objective of this study was to identify signaling components that contribute to D816V c-Kit-mediated transformation. SCF stimulates association of p85PI3K with phosphorylated tyrosine 721 of wild-type c-Kit. Phosphatidylinositol 3 kinase (PI3K) subsequently contributes to the activation of Akt and Jnks. In contrast, these studies demonstrated that the D816V c-Kit mutant was constitutively associated with phosphorylated p85PI3K, and, downstream of PI3K, Jnk 1 and Jnk 2 were activated but Akt was not. Interestingly, Erks 1 and 2 were not constitutively activated by D816V c-Kit. Thus, D816V c-Kit maintains the activity of PI3K but not of all signaling pathways activated by wild-type c-Kit. Further, all pathways downstream of PI3K are not constitutively active in MIHC-D816V cells. Studies with a PI3K inhibitor and D816V/Y721F c-Kit, a mutant incapable of recruiting PI3K, indicate that constitutive activation of PI3K through direct recruitment by D816V c-Kit plays a role in factor-independent growth of MIHC and is critical for tumorigenicity.}}, author = {{Chian, R and Young, S and Danilkovitch-Miagkova, A and Rönnstrand, Lars and Ferrao, P and Ashman, L and Linnekin, D}}, issn = {{1528-0020}}, language = {{eng}}, number = {{5}}, pages = {{1365--1373}}, publisher = {{American Society of Hematology}}, series = {{Blood}}, title = {{Phosphatidylinositol 3 kinase contributes to the transformation of hematopoietic cells by the D816V c-Kit mutant}}, url = {{http://www.ncbi.nlm.nih.gov/pubmed/11520784}}, volume = {{98}}, year = {{2001}}, }