Nuclear receptor tyrosine kinase transport and functions in cancer

Hsu, Jennifer L.; Hung, Mien‐Chie

doi:10.1016/bs.acr.2020.04.010

Cited by 22 publications

(33 citation statements)

References 220 publications

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“…Cell surface receptor tyrosine kinases (RTKs) represent the first interface for transduction of the signal from extracellular polypeptide growth factors. In cancer cells, central to RTK functionality is the ability of specific ligands to bind to its receptors and stimulate its tyrosine kinase activity, thus engaging a multitude of signaling cascades [1][2][3]. Among RTK family members, HER family members act as a prototype largely because of their historical perspective and widespread hyperactivation in human cancers as well as their ability to coordinate many cellular processes that cumulatively lead to oncogenesis [1][2][3].…”

Section: The Her Familymentioning

confidence: 99%

“…Although HER3 lacks catalytic activity, it is actively involved in allosteric regulation of interacting HERs (discussed below) and in scaffolding activity and transcriptional functions [3]. These structural features make EGFR, HER2, and HER3 targets of HER ligands for stimulating combinational heterodimerization with other HER members, leading to signaling in a context-dependent manner [1][2][3].…”

Section: The Her Familymentioning

confidence: 99%

“…Upregulation and hyperactivation of HER family members are common in epithelial cancers. In general, HER1-3 overexpression in solid tumors is associated with a poor clinical response and resistance of these tumors to commonly used cancer therapeutics [1][2][3]. In addition, EGFR and HER2 exhibit widespread mutations in extracellular and/or cytoplasmic domains.…”

Section: The Her Familymentioning

confidence: 99%

“…HER1-3 overexpression is common in breast, ovarian, and several other types of solid tumors [1][2][3]. Most of our understanding about EGFR and HER2 overexpression-linked cancerous phenotypes are from studies involving cell surface receptors and associated proximal signaling events.…”

Section: A Broader Significance Of Paks In Egfr and Her2 Signalingmentioning

confidence: 99%

“…Dysregulation of cell surface receptors that transduce extracellular signals as well as cytoskeleton remodeling of cancer cells are two prominent interconnected aspects of oncogenesis. We here therefore briefly summarize the discoveries and significant advances in the areas of human epidermal growth factor receptors (HERs) [1][2][3][4][5][6][7] and p21-activated kinases (PAKs, a class of serine/threonine kinases [8][9][10][11][12][13] as examples of coordinated regulation of molecules in cancer progression. In addition, we discuss how epidermal growth factor receptor (EGFR)-and HER2-driven studies initially discovered the role of the PAK pathway in conferring invasiveness to breast cancer cells, thereby PAKs making an inroad to cancer biology and revealing the significance of PAKs in cancer progression and metastasis.…”

Section: Introductionmentioning

confidence: 99%

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Coordinated dysregulation of cancer progression by the HER family and p21-activated kinases

Kumar

Paul

Revikumar

et al. 2020

Cancer Metastasis Rev

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Most epithelial cancer types are polygenic in nature and are driven by coordinated dysregulation of multiple regulatory pathways, genes, and protein modifications. The process of coordinated regulation of cancer promoting pathways in response to extrinsic and intrinsic signals facilitates the dysregulation of several pathways with complementary functions, contributing to the hallmarks of cancer. Dysregulation and hyperactivation of cell surface human epidermal growth factor receptors (HERs) and cytoskeleton remodeling by p21-activated kinases (PAKs) are two prominent interconnected aspects of oncogenesis. We briefly discuss the discoveries and significant advances in the area of coordinated regulation of HERs and PAKs in the development and progression of breast and other epithelial cancers. We also discuss how initial studies involving heregulin signaling via HER3-HER2 axis and HER2-overexpressing breast cancer cells not only discovered a mechanistic role of PAK1 in breast cancer pathobiology but also acted as a bridge in generating a broader cancer research interest in other PAK family members and cancer types and catalyzed establishing the role of PAKs in human cancer, at-large. In addition, growth factor stimulation of the PAK pathway also helped to recognize new facets of PAKs, connecting the PAK pathway to oncogenesis, nuclear signaling, gene expression, mitotic progression, DNA damage response, among other phenotypic responses, and shaped the field of PAK cancer research. Finally, we recount some of the current limitations of HER-and PAK-directed therapeutics in counteracting acquired therapeutic resistance and discuss how cancer's as a polygenic disease may be best targeted with a polygenic approach.

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Section: The Her Familymentioning

confidence: 99%

Section: The Her Familymentioning

confidence: 99%

Section: The Her Familymentioning

confidence: 99%

Section: A Broader Significance Of Paks In Egfr and Her2 Signalingmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Coordinated dysregulation of cancer progression by the HER family and p21-activated kinases

Kumar

Paul

Revikumar

et al. 2020

Cancer Metastasis Rev

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Transport of CLCA2 to the nucleus by extracellular vesicles controls keratinocyte survival and migration

Seltmann,

Hettich,

Abele

et al. 2024

J of Extracellular Vesicle

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Chloride channel accessory 2 (CLCA2) is a transmembrane protein, which promotes adhesion of keratinocytes and their survival in response to hyperosmotic stress. Here we show that CLCA2 is transported to the nucleus of keratinocytes via extracellular vesicles. The nuclear localization is functionally relevant, since wild‐type CLCA2, but not a mutant lacking the nuclear localization signal, suppressed migration of keratinocytes and protected them from hyperosmotic stress‐induced cell death. In the nucleus, CLCA2 bound to and activated β‐catenin, resulting in enhanced expression of Wnt target genes. Mass‐spectrometry‐based interaction screening and functional rescue studies identified RNA binding protein 3 as a key effector of nuclear CLCA2. This is of likely relevance in vivo because both proteins co‐localize in the human epidermis. Together, these results identify an unexpected nuclear function of CLCA2 in keratinocytes under homeostatic and stress conditions and suggest a role of extracellular vesicles and their nuclear transport in the control of key cellular activities.

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