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Growth hormone receptor lipid raft l...

Yang, Ning.

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Growth hormone receptor lipid raft localization and mechanisms of growth hormone signaling initiation.

紀錄類型:	書目-語言資料,印刷品 : Monograph/item
正題名/作者:	Growth hormone receptor lipid raft localization and mechanisms of growth hormone signaling initiation./
作者:	Yang, Ning.
面頁冊數:	134 p.
附註:	Adviser: Stuart J. Frank.
Contained By:	Dissertation Abstracts International68-02B.
標題:	Biology, Cell. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3253083

Growth hormone receptor lipid raft localization and mechanisms of growth hormone signaling initiation.
Yang, Ning.

Growth hormone receptor lipid raft localization and mechanisms of growth hormone signaling initiation. - 134 p.

Adviser: Stuart J. Frank.

Thesis (Ph.D.)--The University of Alabama at Birmingham, 2006.

GH is the major regulator for postnatal growth. It exerts its somatogenic and metabolic effects on target tissues by binding to the GHR. The GHR is a transmembrane glycoprotein and belongs to the cytokine receptor superfamily. It undergoes GH-independent dimerization and GH binding induces conformational changes of the receptor, which result in activation of JAK2. Among the major signaling cascades activated by JAK2 in response to GH are STAT5 and ERK1/2 pathways. In this dissertation, we first examined the role of lipid rafts/caveolae, which are cholesterol-rich microdomains in the plasma membrane, in GH signaling. By subcellular fractionation of GH responsive cells, we found that GHR was dramatically concentrated in the raft/caveola fraction. While ERK1/2 and Grb2 were enriched in rafts/caveolae to some degree, STAT5 was almost excluded from the membranous fractions. Disrupting lipid rafts/caveolae resulted in dampened GH-induced ERK1/2 activation. However, neither STAT5 nor JAK2 activation by GH was affected. These data suggested that GHR localization in the lipid rafts/caveolae is important for its signaling. We further looked for determinant(s) for the raft localization of the receptor and found that the ECD is both required and sufficient for GHR association with rafts/caveolae. In the second study, we examined predimerization of the GHR. The TMD has been suggested to mediate this predimerization and its length was proposed to influence the register of the JAK2 associated with the receptor. We investigated the role of the GHR TMD in the predimerization and GH-induced signaling. We found that the native TMD was not required for the ligand-independent dimerization. Instead, our results implicated the "dimerization interface" in the ECD in this association. Moreover, chimeric receptors with a TMD from the LDLR exhibited normal GH-induced signaling. However, signaling by these chimeras was less sensitive to inhibition by a monoclonal antibody and the chimeras were relatively defective in inducible proteolysis. These data indicated that changes of the TMD alter conformation of the ECD, which affects some aspects of GHR function but leaves receptor predirnerization and GH-induced signaling unchanged. Our findings in this dissertation contribute to the understanding of mechanisms of the initiation and regulation of GH signaling.Subjects--Topical Terms:

1017686
Biology, Cell.

Growth hormone receptor lipid raft localization and mechanisms of growth hormone signaling initiation.
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245 1 0 $a Growth hormone receptor lipid raft localization and mechanisms of growth hormone signaling initiation.
300 $a 134 p.
500 $a Adviser: Stuart J. Frank.
500 $a Source: Dissertation Abstracts International, Volume: 68-02, Section: B, page: 0718.
502 $a Thesis (Ph.D.)--The University of Alabama at Birmingham, 2006.
520 $a GH is the major regulator for postnatal growth. It exerts its somatogenic and metabolic effects on target tissues by binding to the GHR. The GHR is a transmembrane glycoprotein and belongs to the cytokine receptor superfamily. It undergoes GH-independent dimerization and GH binding induces conformational changes of the receptor, which result in activation of JAK2. Among the major signaling cascades activated by JAK2 in response to GH are STAT5 and ERK1/2 pathways. In this dissertation, we first examined the role of lipid rafts/caveolae, which are cholesterol-rich microdomains in the plasma membrane, in GH signaling. By subcellular fractionation of GH responsive cells, we found that GHR was dramatically concentrated in the raft/caveola fraction. While ERK1/2 and Grb2 were enriched in rafts/caveolae to some degree, STAT5 was almost excluded from the membranous fractions. Disrupting lipid rafts/caveolae resulted in dampened GH-induced ERK1/2 activation. However, neither STAT5 nor JAK2 activation by GH was affected. These data suggested that GHR localization in the lipid rafts/caveolae is important for its signaling. We further looked for determinant(s) for the raft localization of the receptor and found that the ECD is both required and sufficient for GHR association with rafts/caveolae. In the second study, we examined predimerization of the GHR. The TMD has been suggested to mediate this predimerization and its length was proposed to influence the register of the JAK2 associated with the receptor. We investigated the role of the GHR TMD in the predimerization and GH-induced signaling. We found that the native TMD was not required for the ligand-independent dimerization. Instead, our results implicated the "dimerization interface" in the ECD in this association. Moreover, chimeric receptors with a TMD from the LDLR exhibited normal GH-induced signaling. However, signaling by these chimeras was less sensitive to inhibition by a monoclonal antibody and the chimeras were relatively defective in inducible proteolysis. These data indicated that changes of the TMD alter conformation of the ECD, which affects some aspects of GHR function but leaves receptor predirnerization and GH-induced signaling unchanged. Our findings in this dissertation contribute to the understanding of mechanisms of the initiation and regulation of GH signaling.
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