Protein phosphatase-2A association with microtubules and its role in restricting the invasiveness of human head and neck squamous cell carcinoma cells

Meisinger, Jeremy; Patel, Snehal G.; Vellody, K.; Bergstrom, Richard; Benefield, Janet; Lozano, Yvonne; Young, Matthew R.

doi:10.1016/s0304-3835(96)04517-x

Cited by 26 publications

(25 citation statements)

References 29 publications

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“…The increased migration as a result of reduced PP-2A activity is not unique to LLC variants because we had shown previously that inhibiting PP-2A stimulates the migration of primary cultures of human squamous cell carcinomas of the head and neck. 33 We had also shown increased migration by endothelial cells whose PP-2A is diminished in response to tumor-derived angiogenic factors or whose PP-2A activity is inhibited pharmacologically. 34,25 In identifying the mechanisms by which the decline in PP-2A stimulates tumor migration, our studies showed paxillin serine hyperphosphorylation and tyrosine dephosphorylation, and dissolution of the FAK/Src/paxillin complexes that are important in stabilizing cellular adhesions.…”

Section: Discussionmentioning

confidence: 93%

Protein phosphatase‐2A restricts migration of Lewis lung carcinoma cells by modulating the phosphorylation of focal adhesion proteins

Young

Liu

Meisinger

2002

Intl Journal of Cancer

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The process of metastasis requires migration of tumor cells from the primary tumor into the vasculature and the target tissue. 1 Studies with a variety of tumor types have shown that metastatic tumor cells are more highly motile than are nonmetastatic cells. [2][3][4][5] Cellular migration is influenced by the degree of adhesiveness to a substratum, signaling through integrins, and active turnover of focal adhesions. 6,7 There is, however, a fine balance between adherence/detachment and motility. A strong shift toward focal adhesion formation results in strong adherence with little migration, whereas excessive loss of adherence results in the inability to navigate across the substratum. Interactions with a substratum leads to the formation and stabilization of focal adhesions, where the actin skeleton converges with integrins and an interconnection of protein complexes. 6,8 Among the focal adhesion proteins that mediates communication through integrins during interaction with the substratum is the cytosolic tyrosine kinase FAK. 6,9 When FAK activity is reduced, cellular adhesiveness is diminished 10. During motility, the levels of membrane-associated FAK decline. 11 In adherent cells, FAK is complexed with Src within stable focal adhesions. 6 The tyrosine kinase Src (pp60c-Src) is a prototype of a family of tyrosine kinases that also includes Fyn, Lyn, Yes. Src Y527 residue (Y530 in humans) regulates Src activity. 7,12 When phosphorylated, Y527 inactivates Src by undergoing a conformational change and binding with the Src SH2 domain. FAK complexing with Src is important in Src activation and stabilization of focal adhesions, Src activation can also increase turnover of focal adhesions and increase motility. [13][14][15] An in vivo role of FAK or Src in cancer invasion has been suggested by their increased levels in malignancies. 16 Key in the formation of stable adhesions is association of FAK and Src with paxillin. Paxillin is a 68 kDa adaptor protein that binds a multitude of structural and signaling molecules within focal adhesions. The ability of paxillin to facilitate interaction between molecules of the focal adhesions is regulated by its level of serine and tyrosine phosphorylation. 17 Focal adhesion formation and cellular adhesion are accompanied by tyrosine phosphorylation of paxillin, 18,19 whereas the breakdown of focal adhesions and loss of adherence are accompanied by tyrosine dephosphorylation of paxillin. 20,21 Blocking tyrosine phosphorylation of paxillin results in failure to form organized stress fibers and focal adhesions, and defective cellular adherence. 22 In contrast, serine phosphorylation of paxillin has been associated with redistribution of paxillin from the tyrosine-phosphorylated focal adhesions and increased cell scattering. 23 Our studies with a murine Lewis lung carcinoma model have shown regulation of cell migration by the serine/threonine protein phosphatase PP-2A. 3,24 More highly motile and metastatic tumor cells have diminished PP-2A activity. Inhibition of PP-2A activity wit...

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Section: Discussionmentioning

confidence: 93%

Protein phosphatase‐2A restricts migration of Lewis lung carcinoma cells by modulating the phosphorylation of focal adhesion proteins

Young

Liu

Meisinger

2002

Intl Journal of Cancer

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“…Inhibition of PP-2A with okadaic acid reduced increased invasion of HNSCCC lines through laminin and vitronectin. Increasing PP-2A activity with either ceramide or dihydroxyvitamin D 3 decreased invasion through these matrix components [86,87].…”

Section: Invasion Into Local Stroma and Vascular Systemmentioning

confidence: 97%

The Biology of Distant Metastases in Head and Neck Cancer

Petruzzelli

2001

ORL

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The detection and treatment of metastatic cancer continues to be a challenge for the head and neck oncologist. Unfortunately, head and neck cancer patients who develop distant metastases commonly present late in their course and rapidly succumb to their disease, despite advances in imaging technologies and increased sophistication of biochemical analyses. The development of a rational approach to detection and treatment of metastatic head and neck cancers should begin with an understanding of how these tumors occur and which patients are at greatest risk for developing them. This article presents an overview of the biological processes resulting in the speed of a malignancy from one site to another, with particular attention to head and neck carcinomas. The basic histopathologic, immunology and biochemical abnormalities associated with the development of these secondary tumors are also discussed.

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“…Changes in MT patterns mediated by deregulation of PP2A contribute to increased cell motility and invasiveness in various cell types [13,98,101]. OA treatment of human head and neck squamous cell carcinoma cells results in a loss of MT-bound PP2A pools and increased cell invasiveness [11]. Fostriecin induces abnormal centrosome replication and the formation of aberrant mitotic spindles in Chinese hamster ovary cells [102].…”

Section: Pp2a and Microtubulesmentioning

confidence: 99%

“…Transformation of cells requires notable changes in their cytoskeletal organization and adhesive properties. Not surprisingly, decreased PP2A activity observed in human head and neck squamous carcinoma [11,12], metastatic Lewis lung carcinoma [13] and melanoma BL6 [14] cells is associated with increased cell motility and invasiveness. OA-mediated PP2A inhibition also enhances cell…”

Section: Introductionmentioning

confidence: 99%

Regulation of cell adhesion by PP2A and SV40 small tumor antigen: An important link to cell transformation

Sontag

2006

Cell. Mol. Life Sci.

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The serine/threonine protein phosphatase 2A (PP2A) represents a large family of highly conserved heterotrimeric enzymes. Their critical importance in cell homeostasis is underlined by the fact that they are targets of natural toxins like the tumor promoter okadaic acid, and of simian virus 40 small tumor antigen (SV40 small t), a viral protein known to promote cell transformation. Furthermore, mutated or lower expression levels of PP2A subunits have been found in certain cancers. One major known event in PP2A-dependent cell transformation is the alteration of key signaling pathways that control cell growth and survival. In this review, we focus on how PP2A enzymes also affect cell adhesion and cytoskeletal dynamics, the disruption of which is linked to loss of cell polarity, increased cell motility and invasiveness. We also examine how those various pathways participate in the transforming activity of SV40 small t.

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Protein phosphatase-2A association with microtubules and its role in restricting the invasiveness of human head and neck squamous cell carcinoma cells

Cited by 26 publications

References 29 publications

Protein phosphatase‐2A restricts migration of Lewis lung carcinoma cells by modulating the phosphorylation of focal adhesion proteins

Protein phosphatase‐2A restricts migration of Lewis lung carcinoma cells by modulating the phosphorylation of focal adhesion proteins

The Biology of Distant Metastases in Head and Neck Cancer

Regulation of cell adhesion by PP2A and SV40 small tumor antigen: An important link to cell transformation

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