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Platelet-Derived Growth Factor Recep...

Wu, Kuanlin.

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Platelet-Derived Growth Factor Receptor Beta Activates Abl2 Through Direct Binding and Phosphorylation.

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	Platelet-Derived Growth Factor Receptor Beta Activates Abl2 Through Direct Binding and Phosphorylation./
作者:	Wu, Kuanlin.
出版者:	Ann Arbor : ProQuest Dissertations & Theses, : 2021,
面頁冊數:	110 p.
附註:	Source: Dissertations Abstracts International, Volume: 83-02, Section: B.
Contained By:	Dissertations Abstracts International83-02B.
標題:	Biochemistry. -
電子資源:	https://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=28322273
ISBN:	9798522999728

Platelet-Derived Growth Factor Receptor Beta Activates Abl2 Through Direct Binding and Phosphorylation.
Wu, Kuanlin.

Platelet-Derived Growth Factor Receptor Beta Activates Abl2 Through Direct Binding and Phosphorylation. - Ann Arbor : ProQuest Dissertations & Theses, 2021 - 110 p.

Source: Dissertations Abstracts International, Volume: 83-02, Section: B.

Thesis (Ph.D.)--Yale University, 2021.

This item must not be sold to any third party vendors.

The catalytic activity of Abl family kinases is tightly regulated in cells by a complex set of intra- and intermolecular interactions and post-translational modifications. Abl family kinases are activated by diverse cellular stimuli, including receptor tyrosine kinase signaling. For example, the platelet-derived growth factor receptor beta (PDGFRβ) is a potent activator of Abl family kinases. However, the molecular mechanism by which PDGFRβ engages and activates Abl family kinases is not known. We find that the Abl2 Src Homology 2 (SH2) domain directly binds to phospho-tyrosine Y771 in the PDGFRβ cytoplasmic domain. PDGFRβ directly phosphorylates Abl2 N-terminal half on multiple novel sites including Y116, Y139 and Y161 within the SH3 domain, and Y299, Y303 and Y310 on the kinase domain. Y116, Y161, Y272 and Y310 are all located at or near the SH3/SH2-kinase linker interface, which helps maintain Abl family kinases in an auto-inhibited conformation. We found that PDGFRβ-mediated phosphorylation of Abl2 in vitro activates Abl2 kinase activity, but mutation of these four tyrosine (Y116, Y161, Y272 and Y310) to phenylalanine abrogated PDGFRβ-mediated activation of Abl2. These findings reveal how the PDGFRβ engages and phosphorylates Abl2 and how this leads to activation of the kinase, providing a framework to understand how growth factor receptors engage and activate Abl family kinases. Finally, the biological importance of PDGFR-mediated activation on Abl2 is unclear. Our lab recently showed that Abl2 directly binds and phosphorylates the integrin β1 cytoplasmic tail. Here, I provide initial findings suggesting that PDGFR-mediated activation on Abl2 promotes Abl2-integrin β1 interaction and β1 phosphorylation by Abl2. This process also inhibits talin-integrin interaction. Since talin is the most important integrin activator, Abl2 may regulate talin-integrin interaction, and potentially acts as an integrin inactivator. Abl2 acting downstream of PDGFR to regulate integrin activation may provide a mechanism to allow PDGFR to crosstalk with integrin to regulate many processes including cancer metastasis, angiogenesis and embryonic development.

ISBN: 9798522999728Subjects--Topical Terms:

518028
Biochemistry.
Subjects--Index Terms:

Abl Kinase

Platelet-Derived Growth Factor Receptor Beta Activates Abl2 Through Direct Binding and Phosphorylation.
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245 1 0 $a Platelet-Derived Growth Factor Receptor Beta Activates Abl2 Through Direct Binding and Phosphorylation.
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300 $a 110 p.
500 $a Source: Dissertations Abstracts International, Volume: 83-02, Section: B.
500 $a Advisor: Koleske, Anthony J.
502 $a Thesis (Ph.D.)--Yale University, 2021.
506 $a This item must not be sold to any third party vendors.
520 $a The catalytic activity of Abl family kinases is tightly regulated in cells by a complex set of intra- and intermolecular interactions and post-translational modifications. Abl family kinases are activated by diverse cellular stimuli, including receptor tyrosine kinase signaling. For example, the platelet-derived growth factor receptor beta (PDGFRβ) is a potent activator of Abl family kinases. However, the molecular mechanism by which PDGFRβ engages and activates Abl family kinases is not known. We find that the Abl2 Src Homology 2 (SH2) domain directly binds to phospho-tyrosine Y771 in the PDGFRβ cytoplasmic domain. PDGFRβ directly phosphorylates Abl2 N-terminal half on multiple novel sites including Y116, Y139 and Y161 within the SH3 domain, and Y299, Y303 and Y310 on the kinase domain. Y116, Y161, Y272 and Y310 are all located at or near the SH3/SH2-kinase linker interface, which helps maintain Abl family kinases in an auto-inhibited conformation. We found that PDGFRβ-mediated phosphorylation of Abl2 in vitro activates Abl2 kinase activity, but mutation of these four tyrosine (Y116, Y161, Y272 and Y310) to phenylalanine abrogated PDGFRβ-mediated activation of Abl2. These findings reveal how the PDGFRβ engages and phosphorylates Abl2 and how this leads to activation of the kinase, providing a framework to understand how growth factor receptors engage and activate Abl family kinases. Finally, the biological importance of PDGFR-mediated activation on Abl2 is unclear. Our lab recently showed that Abl2 directly binds and phosphorylates the integrin β1 cytoplasmic tail. Here, I provide initial findings suggesting that PDGFR-mediated activation on Abl2 promotes Abl2-integrin β1 interaction and β1 phosphorylation by Abl2. This process also inhibits talin-integrin interaction. Since talin is the most important integrin activator, Abl2 may regulate talin-integrin interaction, and potentially acts as an integrin inactivator. Abl2 acting downstream of PDGFR to regulate integrin activation may provide a mechanism to allow PDGFR to crosstalk with integrin to regulate many processes including cancer metastasis, angiogenesis and embryonic development.
590 $a School code: 0265.
650 4 $a Biochemistry. $3 518028
650 4 $a Cellular biology. $3 3172791
650 4 $a Cancer. $3 634186
650 4 $a Collaboration. $3 3556296
650 4 $a Cytoskeleton. $3 549552
650 4 $a Leukemia. $3 677274
650 4 $a Mutation. $3 837917
650 4 $a DNA damage. $3 916185
650 4 $a Binding sites. $3 3560349
650 4 $a Adhesion. $3 818212
650 4 $a Scientific imaging. $3 3560377
650 4 $a Peptides. $3 605772
650 4 $a Kinases. $3 3558077
650 4 $a Competition. $3 537031
650 4 $a Proteins. $3 558769
650 4 $a Crystal structure. $3 3561040
650 4 $a T cell receptors. $3 3561758
650 4 $a Mass spectrometry. $3 551172
650 4 $a Signal transduction. $3 3546420
650 4 $a Regulation. $3 3561775
650 4 $a Lymphocytes. $3 895384
650 4 $a Chromosomes. $3 638948
650 4 $a Ligands. $3 686413
650 4 $a Phosphorylation. $3 816803
650 4 $a Cell growth. $3 3560747
650 4 $a Roles. $3 3559999
650 4 $a Interfaces. $2 gtt $3 834756
653 $a Abl Kinase
653 $a Kinase regulation
653 $a Platelet-derived growth factor receptor beta
690 $a 0487
690 $a 0379
710 2 $a Yale University. $b Molecular Biophysics and Biochemistry. $3 3540261
773 0 $t Dissertations Abstracts International $g 83-02B.
790 $a 0265
791 $a Ph.D.
792 $a 2021
793 $a English
856 4 0 $u https://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=28322273