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Phosphoregulation of NEK3 Kinase in ...

Schulhaus, Katherine M.

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Phosphoregulation of NEK3 Kinase in the Pathogenesis of Human Breast Carcinoma.

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	Phosphoregulation of NEK3 Kinase in the Pathogenesis of Human Breast Carcinoma./
作者:	Schulhaus, Katherine M.
出版者:	Ann Arbor : ProQuest Dissertations & Theses, : 2017,
面頁冊數:	284 p.
附註:	Source: Dissertation Abstracts International, Volume: 78-08(E), Section: B.
Contained By:	Dissertation Abstracts International78-08B(E).
標題:	Molecular biology. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=10252716
ISBN:	9781369678888

Phosphoregulation of NEK3 Kinase in the Pathogenesis of Human Breast Carcinoma.
Schulhaus, Katherine M.

Phosphoregulation of NEK3 Kinase in the Pathogenesis of Human Breast Carcinoma. - Ann Arbor : ProQuest Dissertations & Theses, 2017 - 284 p.

Source: Dissertation Abstracts International, Volume: 78-08(E), Section: B.

Thesis (Ph.D.)--Northwestern University, 2017.

The polypeptide hormone prolactin (PRL) is increasingly recognized as contributing to the development and progression of human breast cancer. This is supported by epidemiologic studies that found women with high levels of serum PRL are at an increased risk for developing breast cancer. Activation of the prolactin receptor (PRLR) by PRL contributes to the growth, survival and motility of human breast cancer cells. PRL has been shown to act as a chemoattractant for breast cancer cells, accompanied by reorganization of the cytoskeleton. However, the molecular mechanisms by which PRL induces cytoskeletal rearrangement and regulates cell migration/invasion are not well defined. Therefore, elucidation of the downstream signaling pathways that contribute to PRL stimulated breast cancer cell motility and invasion is of great importance.

ISBN: 9781369678888Subjects--Topical Terms:

517296
Molecular biology.

Phosphoregulation of NEK3 Kinase in the Pathogenesis of Human Breast Carcinoma.
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520 $a The polypeptide hormone prolactin (PRL) is increasingly recognized as contributing to the development and progression of human breast cancer. This is supported by epidemiologic studies that found women with high levels of serum PRL are at an increased risk for developing breast cancer. Activation of the prolactin receptor (PRLR) by PRL contributes to the growth, survival and motility of human breast cancer cells. PRL has been shown to act as a chemoattractant for breast cancer cells, accompanied by reorganization of the cytoskeleton. However, the molecular mechanisms by which PRL induces cytoskeletal rearrangement and regulates cell migration/invasion are not well defined. Therefore, elucidation of the downstream signaling pathways that contribute to PRL stimulated breast cancer cell motility and invasion is of great importance.
520 $a The PRL/PRLR complex activates multiple signaling pathways, including the serine/threonine kinase, NEK3 (NIMA-related kinase 3). In vitro studies have implicated a role for NEK3 in the regulation of breast cancer cell migration, invasion, and the actin cytoskeletal reorganization necessary for these processes. However, the specific mechanisms of NEK3 activation in response to PRL signaling have not been defined. In this work, a novel PRL-inducible regulatory phosphorylation site within the activation segment of NEK3, threonine-165 (Thr-165), was identified. Phosphorylation at NEK3 Thr-165 was found to be dependent on activation of the extracellular signal-regulated kinase 1/2 (ERK1/2) signaling pathway using both pharmacological inhibition and siRNA-mediated knockdown approaches. Strikingly, inhibition of phosphorylation at NEK3 Thr-165 by expression of a phospho-deficient mutant (NEK3-T165V) resulted in increased focal adhesion size, formation of zyxin-positive focal adhesions, and reorganization of the actin cytoskeleton into stress fibers. Concordantly, NEK3-T165V cells exhibited migratory defects. Additionally, the focal adhesion adaptor protein paxillin (PXN) was identified as a potential substrate of NEK3 and we show that NEK3 phosphorylates PXN at residue Thr-401 within the LIM2 domain. Furthermore, it was demonstrated that expression of a phospho-deficient PXN mutant (PXN-T401V) resulted in inhibition of cell migration. Together, these data support a modulatory role for phosphorylation at NEK3 Thr-165 in focal adhesion maturation and/or turnover to promote breast cancer cell migration.
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