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Substrate stiffness and the receptor-type tyrosine-protein phosphatase alpha regulate spreading of colon cancer cells through cytoskeletal contractility

Oncogene volume 29, pages 2724–2738 (2010)Cite this article

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Abstract

Microenvironmental clues are critical to cell behavior. One of the key elements of migration is the generation and response to forces. Up to now, there is no definitive concept on how the generation and responses to cellular forces influence cancer-cell behavior. Here, we show that expression of receptor-type tyrosine-protein phosphatase alpha (RPTPα) in human SW480 colon cancer cells sets a threshold for the response to matrix forces by changing cellular contractility. This can be explained as an RPTPα-mediated increase in contractility with a consecutive increase in number and size of adhesion sites and stress fibers. These effects are mediated through myosin light chain kinase and largely independent of Rho/Rho-kinase (ROCK) signaling. In addition, we report that RPTPα influences spreading on low-rigidity surfaces, binding of collagen-coated beads and expression of RPTPα is required for invasion into the chorioallantoic membrane. These data suggest that force-responsive proteins such as RPTPα can influence cancer-cell behavior and identify potential targets for cancer therapy.

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Abbreviations

CAM:

chorioallantoic membrane

CSK:

C-terminal Src kinase

ECM:

extracellular matrix

FC:

focal contact

GFP:

green fluorescent protein

MLCK:

myosin light chain kinase

MLC:

myosin light chain

MYPT1:

myosin phosphatase target subunit isoform 1

ROCK:

Rho kinase

RPTPα:

receptor-type tyrosine-protein phosphatase alpha

SFK:

Src family kinases

TMA:

Tissue micro-array

YFP:

yellow fluorescent protein

References

  • Ardini E, Agresti R, Tagliabue E, Greco M, Aiello P, Yang LT et al. (2000). Expression of protein tyrosine phosphatase alpha (RPTPalpha) in human breast cancer correlates with low tumor grade, and inhibits tumor cell growth in vitro and in vivo. Oncogene 19: 4979–4987.

    Article  CAS  Google Scholar 

  • Balaban NQ, Schwarz US, Riveline D, Goichberg P, Tzur G, Sabanay I et al. (2001). Force and focal adhesion assembly: a close relationship studied using elastic micropatterned substrates. Nat Cell Biol 3: 466–472.

    Article  CAS  Google Scholar 

  • Benoliel AM, Pirro N, Marin V, Consentino B, Pierres A, Vitte J et al. (2003). Correlation between invasiveness of colorectal tumor cells and adhesive potential under flow. Anticancer Res 23: 4891–4896.

    PubMed  Google Scholar 

  • Berndt A, Luo X, Bohmer FD, Kosmehl H . (1999). Expression of the transmembrane protein tyrosine phosphatase RPTPalpha in human oral squamous cell carcinoma. Histochem Cell Biol 111: 399–403.

    Article  CAS  Google Scholar 

  • Bodrikov V, Leshchyns'ka I, Sytnyk V, Overvoorde J, den Hertog J, Schachner M . (2005). RPTPalpha is essential for NCAM-mediated p59fyn activation and neurite elongation. J Cell Biol 168: 127–139.

    Article  CAS  Google Scholar 

  • Choquet D, Felsenfeld DP, Sheetz MP . (1997). Extracellular matrix rigidity causes strengthening of integrin-cytoskeleton linkages. Cell 88: 39–48.

    Article  CAS  Google Scholar 

  • den Hertog J, Pals CE, Peppelenbosch MP, Tertoolen LG, de Laat SW, Kruijer W . (1993). Receptor protein tyrosine phosphatase alpha activates pp60c-src and is involved in neuronal differentiation. EMBO J 12: 3789–3798.

    Article  CAS  Google Scholar 

  • Engler AJ, Sen S, Sweeney HL, Discher DE . (2006). Matrix elasticity directs stem cell lineage specification. Cell 126: 677–689.

    Article  CAS  Google Scholar 

  • Han B, Bai XH, Lodyga M, Xu J, Yang BB, Keshavjee S et al. (2004). Conversion of mechanical force into biochemical signaling. J Biol Chem 279: 54793–54801.

    Article  CAS  Google Scholar 

  • Harder KW, Moller NP, Peacock JW, Jirik FR . (1998). Protein-tyrosine phosphatase alpha regulates Src family kinases and alters cell-substratum adhesion. J Biol Chem 273: 31890–31900.

    Article  CAS  Google Scholar 

  • Harris AK, Stopak D, Wild P . (1981). Fibroblast traction as a mechanism for collagen morphogenesis. Nature 290: 249–251.

    Article  CAS  Google Scholar 

  • Ingber DE . (2003). Mechanobiology and diseases of mechanotransduction. Ann Med 35: 564–577.

    Article  Google Scholar 

  • Jiang G, Huang AH, Cai Y, Tanase M, Sheetz MP . (2006). Rigidity sensing at the leading edge through alphavbeta3 integrins and RPTPalpha. Biophys J 90: 1804–1809.

    Article  CAS  Google Scholar 

  • Kostic A, Sheetz MP . (2006). Fibronectin rigidity response through Fyn and p130Cas recruitment to the leading edge. Mol Biol Cell 17: 2684–2695.

    Article  CAS  Google Scholar 

  • Kunzi-Rapp K, Genze F, Kufer R, Reich E, Hautmann RE, Gschwend JE . (2001). Chorioallantoic membrane assay: vascularized 3-dimensional cell culture system for human prostate cancer cells as an animal substitute model. J Urol 166: 1502–1507.

    Article  CAS  Google Scholar 

  • Lee W, Sodek J, McCulloch CA . (1996). Role of integrins in regulation of collagen phagocytosis by human fibroblasts. J Cell Physiol 168: 695–704.

    Article  CAS  Google Scholar 

  • Munevar S, Wang Y, Dembo M . (2001). Traction force microscopy of migrating normal and H-ras transformed 3T3 fibroblasts. Biophys J 80: 1744–1757.

    Article  CAS  Google Scholar 

  • Paszek MJ, Zahir N, Johnson KR, Lakins JN, Rozenberg GI, Gefen A et al. (2005). Tensional homeostasis and the malignant phenotype. Cancer Cell 8: 241–254.

    Article  CAS  Google Scholar 

  • Petrone A, Sap J . (2000). Emerging issues in receptor protein tyrosine phosphatase function: lifting fog or simply shifting? J Cell Sci 113: 2345–2354.

    CAS  PubMed  Google Scholar 

  • Sahai E, Marshall CJ . (2002). ROCK and Dia have opposing effects on adherens junctions downstream of Rho. Nat Cell Biol 4: 408–415.

    Article  CAS  Google Scholar 

  • Sawada Y, Tamada M, Dubin-Thaler BJ, Cherniavskaya O, Sakai R, Tanaka S et al. (2006). Force sensing by mechanical extension of the Src family kinase substrate p130Cas. Cell 127: 1015–1026.

    Article  CAS  Google Scholar 

  • Su J, Muranjan M, Sap J . (1999). Receptor protein tyrosine phosphatase alpha activates Src-family kinases and controls integrin-mediated responses in fibroblasts. Curr Biol 9: 505–511.

    Article  CAS  Google Scholar 

  • Tabiti K, Smith DR, Goh HS, Pallen CJ . (1995). Increased mRNA expression of the receptor-like protein tyrosine phosphatase alpha in late stage colon carcinomas. Cancer Lett 93: 239–248.

    Article  CAS  Google Scholar 

  • Thamilselvan V, Basson MD . (2004). Pressure activates colon cancer cell adhesion by inside-out focal adhesion complex and actin cytoskeletal signaling. Gastroenterology 126: 8–18.

    Article  CAS  Google Scholar 

  • Totsukawa G, Wu Y, Sasaki Y, Hartshorne DJ, Yamakita Y, Yamashiro S et al. (2004). Distinct roles of MLCK and ROCK in the regulation of membrane protrusions and focal adhesion dynamics during cell migration of fibroblasts. J Cell Biol 164: 427–439.

    Article  CAS  Google Scholar 

  • von Wichert G, Jiang G, Kostic A, DeVos K, Sap J, Sheetz MP . (2003). RPTP-alpha acts as a transducer of mechanical force on alphav/beta3-integrin-cytoskeleton linkages. J Cell Biol 161: 143–153.

    Article  CAS  Google Scholar 

  • Wang Y, Botvinick EL, Zhao Y, Berns MW, Usami S, Tsien RY et al. (2005). Visualizing the mechanical activation of Src. Nature 434: 1040–1045.

    Article  CAS  Google Scholar 

  • Wang YL, Pelham Jr RJ . (1998). Preparation of a flexible, porous polyacrylamide substrate for mechanical studies of cultured cells. Methods Enzymol 298: 489–496.

    Article  CAS  Google Scholar 

  • Wells RG . (2008). The role of matrix stiffness in regulating cell behavior. Hepatology 47: 1394–1400.

    Article  CAS  Google Scholar 

  • Wozniak MA, Desai R, Solski PA, Der CJ, Keely PJ . (2003). ROCK-generated contractility regulates breast epithelial cell differentiation in response to the physical properties of a three-dimensional collagen matrix. J Cell Biol 163: 583–595.

    Article  CAS  Google Scholar 

  • Wu CW, Kao HL, Li AF, Chi CW, Lin WC . (2006). Protein tyrosine-phosphatase expression profiling in gastric cancer tissues. Cancer Lett 242: 95–103.

    Article  CAS  Google Scholar 

  • Zeng L, D'Alessandri L, Kalousek MB, Vaughan L, Pallen CJ . (1999). Protein tyrosine phosphatase alpha (PTPalpha) and contactin form a novel neuronal receptor complex linked to the intracellular tyrosine kinase fyn. J Cell Biol 147: 707–714.

    Article  CAS  Google Scholar 

  • Zeng L, Si X, Yu WP, Le HT, Ng KP, Teng RM et al. (2003). PTP alpha regulates integrin-stimulated FAK autophosphorylation and cytoskeletal rearrangement in cell spreading and migration. J Cell Biol 160: 137–146.

    Article  CAS  Google Scholar 

  • Zheng XM, Wang Y, Pallen CJ . (1992). Cell transformation and activation of pp60c-src by overexpression of a protein tyrosine phosphatase. Nature 359: 336–339.

    Article  CAS  Google Scholar 

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Acknowledgements

This work was supported by the DFG to GvW and FO and the Deutsche Krebshilfe to GvW and TS.

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Author notes

  1. D Krndija, H Schmid, T Seufferlein and G von Wichert: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Internal Medicine I, University of Ulm, Ulm, Baden-Wuerttemberg, Germany

    D Krndija, H Schmid, J-L Eismann, U Lother, G Adler, F Oswald, T Seufferlein & G von Wichert

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  1. D Krndija
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  2. H Schmid
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  3. J-L Eismann
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Correspondence to G von Wichert.

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Krndija, D., Schmid, H., Eismann, JL. et al. Substrate stiffness and the receptor-type tyrosine-protein phosphatase alpha regulate spreading of colon cancer cells through cytoskeletal contractility. Oncogene 29, 2724–2738 (2010). https://doi.org/10.1038/onc.2010.25

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