Protein phosphatase 2A interacts with the Src kinase substrate p130CAS

Yokoyama, Noriko; Miller, W. Todd

doi:10.1038/sj.onc.1204735

Cited by 22 publications

(17 citation statements)

References 38 publications

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“…Furthermore, besides Aurora-B, other target kinases of Hesperadin (AMPK, Chk1, Mek1...) are also substrates of PP2A, although at a higher IC 50, which make them candidates for HEF1 phosphorylation [35][36][37]. Furthermore, PP2A dephosphorylates another member of HEF1 docking protein family, p130 Cas [38]. This suggests that PP2A might then target both protein, the Hesperadin sensitive kinase and HEF1.…”

Section: Discussionmentioning

confidence: 99%

Phosphorylation of human enhancer of filamentation (HEF1) on serine 369 induces its proteasomal degradation

Hivert

Pierre

Raingeaud

2009

Biochemical Pharmacology

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Please cite this article as: Hivert V, Pierre J, Raingeaud J, Phosphorylation of human enhancer of filamentation (HEF1) on serine 369 induces its proteasomal degradation, Biochemical Pharmacology (2008Pharmacology ( ), doi:10.1016Pharmacology ( /j.bcp.2009 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Cas family. HEF1 is present at focal adhesions and is involved in integrin signalling mediating cytoskeleton reorganization associated with cell migration, adhesion or apoptosis.HEF1 functions are regulated in part by phosphorylation on tyrosine residues. HEF1 is also phosphorylated on serines/threonines leading to two isoforms refered to as p105 and p115. In most cases, the serine/threonine kinase(s) responsible for HEF1 phosphorylation have not been identified. In the present study, we have investigated HEF1 ser/thr phosphorylation. In the HCT-116 cell line transiently overexpressing Flag-HEF1 we showed that Hesperadin, a synthetic indolinone displaying antiproliferative effect and described as an inhibitor of various kinases including Aurora-B, prevented HEF1 phosphorylation induced by the ser/thr phosphatase PP2A inhibitor : okadaic acid (OA). In addition we showed that conversion of endogenous HEF1 p105 to p115 in HaCaT cells was prevented upon treatment with Hesperadin, resulting in accumulation of p105HEF1. We also identified serine 369 as the target site of phosphorylation by this Hesperadin-inhibited kinase in HCT-116. Finally, we * ManuscriptPage 2 of 37 A c c e p t e d M a n u s c r i p t 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 provide evidence that phosphorylation on serine 369 but not phosphorylation on serine 296, triggers HEF1 degradation by the proteasomal machinery. These data suggest that conversion of p105 to p115 results from a ser-369-dependent phosphorylation mediated by an Hesperadin-sensitive kinase and regulates the half-life of HEF1.Keywords: human enhancer of filamentation 1, protein phosphatase 2A, Hesperadin, protein stability.

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Section: Discussionmentioning

confidence: 99%

Phosphorylation of human enhancer of filamentation (HEF1) on serine 369 induces its proteasomal degradation

Hivert

Pierre

Raingeaud

2009

Biochemical Pharmacology

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“…6,38 Nevertheless, our study has shown that downstream of a decline in PP-2A, as occurs in metastatic cells, is increased serine phosphorylation of paxillin, dissolution of FAK/Src/paxillin focal adhesion complexes that otherwise stabilize cell adhesiveness, and enhanced cellular migration that is dependent on increased Src activity. …”

Section: Discussionmentioning

confidence: 99%

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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“…The interaction of the PP2A-IQGAP1 protein complex with F-actin and integrins is lost in HME cells during the G1 to the G2/M cell cycle transition [75]. Treatment of NIH3T3 cells with OA increases phosphorylation of p130CAS [41], which is necessary for cell entry into mitosis and is maintained until mitosis is complete [76]. These observations suggest that PP2A inhibition is necessary for decreased cell adhesion at focal adhesion sites, and this step is a prerequisite for cell entry into mitosis.…”

Section: Pp2a and Actinmentioning

confidence: 98%

“…Interestingly, BL6 mouse melanoma cells, which express an N-terminally truncated form of B'/B56γ1, are metastatic cells [14]. Besides paxillin, PP2A also directly interacts with and dephosphorylates p130CAS, which regulates cell entry into mitosis [41].…”

Section: Pp2a and Cell-matrix Interactionsmentioning

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 interacts with the Src kinase substrate p130CAS

Cited by 22 publications

References 38 publications

Phosphorylation of human enhancer of filamentation (HEF1) on serine 369 induces its proteasomal degradation

Phosphorylation of human enhancer of filamentation (HEF1) on serine 369 induces its proteasomal degradation

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

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

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