Shc and FAK Differentially Regulate Cell Motility and Directionality Modulated by PTEN

Overview

Journal J Cell Biol

Specialty Cell Biology

Date 1999 Jul 31

PMID 10427092

Citations 126

Authors

J Gu

M Tamura

R Pankov

E H Danen

T Takino

K Matsumoto

K M Yamada

Affiliations

Soon will be listed here.

Abstract

Cell migration is modulated by regulatory molecules such as growth factors, oncogenes, and the tumor suppressor PTEN. We previously described inhibition of cell migration by PTEN and restoration of motility by focal adhesion kinase (FAK) and p130 Crk-associated substrate (p130(Cas)). We now report a novel pathway regulating random cell motility involving Shc and mitogen-activated protein (MAP) kinase, which is downmodulated by PTEN and additive to a FAK pathway regulating directional migration. Overexpression of Shc or constitutively activated MEK1 in PTEN- reconstituted U87-MG cells stimulated integrin- mediated MAP kinase activation and cell migration. Conversely, overexpression of dominant negative Shc inhibited cell migration; Akt appeared uninvolved. PTEN directly dephosphorylated Shc. The migration induced by FAK or p130(Cas) was directionally persistent and involved extensive organization of actin microfilaments and focal adhesions. In contrast, Shc or MEK1 induced a random type of motility associated with less actin cytoskeletal and focal adhesion organization. These results identify two distinct, additive pathways regulating cell migration that are downregulated by tumor suppressor PTEN: one involves Shc, a MAP kinase pathway, and random migration, whereas the other involves FAK, p130(Cas), more extensive actin cytoskeletal organization, focal contacts, and directionally persistent cell motility. Integration of these pathways provides an intracellular mechanism for regulating the speed and the directionality of cell migration.

Citing Articles

-GlcNAcylation of Focal Adhesion Kinase Regulates Cell Adhesion, Migration, and Proliferation via the FAK/AKT Pathway.

Zhang Z, Isaji T, Oyama Y, Liu J, Xu Z, Sun Y Biomolecules. 2025; 14(12.

PMID: 39766284 PMC: 11674061. DOI: 10.3390/biom14121577.

SET8 inhibition preserves PTEN to attenuate kidney cell apoptosis in cisplatin nephrotoxicity.

Yang X, Guan Y, Bayliss G, Zhao T, Zhuang S Res Sq. 2024; .

PMID: 39184108 PMC: 11343278. DOI: 10.21203/rs.3.rs-4603170/v1.

Focal Adhesion Kinase Binds to the HPV E2 Protein to Regulate Initial Replication after Infection.

Jose L, Gonzalez J, Kessinger E, Androphy E, DeSmet M Pathogens. 2023; 12(10).

PMID: 37887719 PMC: 10609836. DOI: 10.3390/pathogens12101203.

Synthetic lethal approaches to target cancers with loss of PTEN function.

Ertay A, Ewing R, Wang Y Genes Dis. 2023; 10(6):2511-2527.

PMID: 37533462 PMC: 7614861. DOI: 10.1016/j.gendis.2022.12.015.

PTEN phosphatase inhibits metastasis by negatively regulating the Entpd5/IGF1R pathway through ATF6.

Yu Y, Dai M, Huang L, Chen W, Yu E, Mendoza A iScience. 2023; 26(2):106070.

PMID: 36824269 PMC: 9942123. DOI: 10.1016/j.isci.2023.106070.

References

CARY L, Han D, Polte T, Hanks S, Guan J . Identification of p130Cas as a mediator of focal adhesion kinase-promoted cell migration. J Cell Biol. 1998; 140(1):211-21. PMC: 2132604. DOI: 10.1083/jcb.140.1.211. View

Di Cristofano A, Pesce B, Cordon-Cardo C, Pandolfi P . Pten is essential for embryonic development and tumour suppression. Nat Genet. 1998; 19(4):348-55. DOI: 10.1038/1235. View

Oliver T, Lee J, Jacobson K . Forces exerted by locomoting cells. Semin Cell Biol. 1994; 5(3):139-47. DOI: 10.1006/scel.1994.1018. View

Li J, Simpson L, Takahashi M, Miliaresis C, Myers M, Tonks N . The PTEN/MMAC1 tumor suppressor induces cell death that is rescued by the AKT/protein kinase B oncogene. Cancer Res. 1998; 58(24):5667-72. View

Steck P, Pershouse M, Jasser S, Yung W, Lin H, Ligon A . Identification of a candidate tumour suppressor gene, MMAC1, at chromosome 10q23.3 that is mutated in multiple advanced cancers. Nat Genet. 1997; 15(4):356-62. DOI: 10.1038/ng0497-356. View

Wary K, Mainiero F, Isakoff S, Marcantonio E, Giancotti F . The adaptor protein Shc couples a class of integrins to the control of cell cycle progression. Cell. 1996; 87(4):733-43. DOI: 10.1016/s0092-8674(00)81392-6. View

Stambolic V, Suzuki A, de la Pompa J, Brothers G, Mirtsos C, Sasaki T . Negative regulation of PKB/Akt-dependent cell survival by the tumor suppressor PTEN. Cell. 1998; 95(1):29-39. DOI: 10.1016/s0092-8674(00)81780-8. View

Maehama T, Dixon J . The tumor suppressor, PTEN/MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol 3,4,5-trisphosphate. J Biol Chem. 1998; 273(22):13375-8. DOI: 10.1074/jbc.273.22.13375. View

Shalev N, Wong M, Mills G, Yount G, Stokoe D . Protein kinase B (PKB/Akt) activity is elevated in glioblastoma cells due to mutation of the tumor suppressor PTEN/MMAC. Curr Biol. 1998; 8(21):1195-8. DOI: 10.1016/s0960-9822(07)00493-9. View

10.

Yenush L, Kundra V, White M, Zetter B . Functional domains of the insulin receptor responsible for chemotactic signaling. J Biol Chem. 1994; 269(1):100-4. View

11.

Ware M, Wells A, Lauffenburger D . Epidermal growth factor alters fibroblast migration speed and directional persistence reciprocally and in a matrix-dependent manner. J Cell Sci. 1998; 111 ( Pt 16):2423-32. DOI: 10.1242/jcs.111.16.2423. View

12.

Zigmond S . Recent quantitative studies of actin filament turnover during cell locomotion. Cell Motil Cytoskeleton. 1993; 25(4):309-16. DOI: 10.1002/cm.970250402. View

13.

Schlaepfer D, Hanks S, Hunter T, van der Geer P . Integrin-mediated signal transduction linked to Ras pathway by GRB2 binding to focal adhesion kinase. Nature. 1994; 372(6508):786-91. DOI: 10.1038/372786a0. View

14.

Sieg D, Ilic D, Jones K, Damsky C, Hunter T, Schlaepfer D . Pyk2 and Src-family protein-tyrosine kinases compensate for the loss of FAK in fibronectin-stimulated signaling events but Pyk2 does not fully function to enhance FAK- cell migration. EMBO J. 1998; 17(20):5933-47. PMC: 1170921. DOI: 10.1093/emboj/17.20.5933. View

15.

Li D, Sun H . PTEN/MMAC1/TEP1 suppresses the tumorigenicity and induces G1 cell cycle arrest in human glioblastoma cells. Proc Natl Acad Sci U S A. 1998; 95(26):15406-11. PMC: 28055. DOI: 10.1073/pnas.95.26.15406. View

16.

CARY L, Chang J, Guan J . Stimulation of cell migration by overexpression of focal adhesion kinase and its association with Src and Fyn. J Cell Sci. 1996; 109 ( Pt 7):1787-94. DOI: 10.1242/jcs.109.7.1787. View

17.

Tamura M, Gu J, Danen E, Takino T, Miyamoto S, Yamada K . PTEN interactions with focal adhesion kinase and suppression of the extracellular matrix-dependent phosphatidylinositol 3-kinase/Akt cell survival pathway. J Biol Chem. 1999; 274(29):20693-703. DOI: 10.1074/jbc.274.29.20693. View

18.

Reiske H, Kao S, CARY L, Guan J, Lai J, Chen H . Requirement of phosphatidylinositol 3-kinase in focal adhesion kinase-promoted cell migration. J Biol Chem. 1999; 274(18):12361-6. DOI: 10.1074/jbc.274.18.12361. View

19.

Tamura M, Gu J, Takino T, Yamada K . Tumor suppressor PTEN inhibition of cell invasion, migration, and growth: differential involvement of focal adhesion kinase and p130Cas. Cancer Res. 1999; 59(2):442-9. View

20.

Huttenlocher A, Sandborg R, Horwitz A . Adhesion in cell migration. Curr Opin Cell Biol. 1995; 7(5):697-706. DOI: 10.1016/0955-0674(95)80112-x. View