The Ser/Thr Kinase MAP4K4 Drives C-Met-induced Motility and Invasiveness in a Cell-based Model of SHH Medulloblastoma

Overview

Journal Springerplus

Date 2015 Jan 28

PMID 25625039

Citations 19

Authors

Karthiga Santhana Kumar

Dimitra Tripolitsioti

Min Ma

Jasmin Grahlert

Katja B Egli

Giulio Fiaschetti

Tarek Shalaby

Michael A Grotzer

Martin Baumgartner

Affiliations

Soon will be listed here.

Abstract

Medulloblastoma (MB) comprises four molecularly and genetically distinct subgroups of embryonal brain tumors that develop in the cerebellum. MB mostly affects infants and children and is difficult to treat because of frequent dissemination of tumor cells within the leptomeningeal space. A potential promoter of cell dissemination is the c-Met proto-oncogene receptor tyrosine kinase, which is aberrantly expressed in many human tumors including MB. Database analysis showed that c-Met is highly expressed in the sonic hedgehog (SHH) subgroup and in a small subset of Group 3 and Group 4 MB tumors. Using a cell-based three-dimensional cell motility assay combined with live-cell imaging, we investigated whether the c-Met ligand HGF could drive dissemination of MB cells expressing high levels of c-Met, and determined downstream effector mechanisms of this process. We detected variable c-Met expression in different established human MB cell lines, and we found that in lines expressing high c-Met levels, HGF promoted cell dissemination and invasiveness. Specifically, HGF-induced c-Met activation enhanced the capability of the individual cells to migrate in a JNK-dependent manner. Additionally, we identified the Ser/Thr kinase MAP4K4 as a novel driver of c-Met-induced invasive cell dissemination. This increased invasive motility was due to MAP4K4 control of F-actin dynamics in structures required for migration and invasion. Thus, MAP4K4 couples growth factor signaling to actin cytoskeleton regulation in tumor cells, suggesting that MAP4K4 could present a promising novel target to be evaluated for treating growth factor-induced dissemination of MB tumors of different subgroups and of other human cancers.

Citing Articles

MAP4K4 regulates forces at cell-cell and cell-matrix adhesions to promote collective cell migration.

Delsin L, Plutoni C, Clouvel A, Keil S, Marpeaux L, Elouassouli L Life Sci Alliance. 2023; 6(9).

PMID: 37369604 PMC: 10300198. DOI: 10.26508/lsa.202302196.

MAP4K4 and cancer: ready for the main stage?.

Gonzalez-Montero J, Rojas C, Burotto M Front Oncol. 2023; 13:1162835.

PMID: 37223681 PMC: 10200945. DOI: 10.3389/fonc.2023.1162835.

Abrogation of MAP4K4 protein function causes congenital anomalies in humans and zebrafish.

Patterson V, Ullah F, Bryant L, Griffin J, Sidhu A, Saliganan S Sci Adv. 2023; 9(17):eade0631.

PMID: 37126546 PMC: 10132768. DOI: 10.1126/sciadv.ade0631.

The molecular basis of the dichotomous functionality of MAP4K4 in proliferation and cell motility control in cancer.

Jovanovic D, Yan S, Baumgartner M Front Oncol. 2022; 12:1059513.

PMID: 36568222 PMC: 9774001. DOI: 10.3389/fonc.2022.1059513.

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Grundy M, Narendran A Front Pediatr. 2022; 10:910268.

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References

Han Z, Boyle D, Chang L, Bennett B, Karin M, Yang L . c-Jun N-terminal kinase is required for metalloproteinase expression and joint destruction in inflammatory arthritis. J Clin Invest. 2001; 108(1):73-81. PMC: 209341. DOI: 10.1172/JCI12466. View

Liang J, Wang H, Rashid A, Tan T, Hwang R, Hamilton S . Expression of MAP4K4 is associated with worse prognosis in patients with stage II pancreatic ductal adenocarcinoma. Clin Cancer Res. 2008; 14(21):7043-9. DOI: 10.1158/1078-0432.CCR-08-0381. View

Orian-Rousseau V, Chen L, Sleeman J, Herrlich P, Ponta H . CD44 is required for two consecutive steps in HGF/c-Met signaling. Genes Dev. 2002; 16(23):3074-86. PMC: 187488. DOI: 10.1101/gad.242602. View

Hao J, Chen J, Sui H, Si-Ma X, Li G, Liu C . A five-gene signature as a potential predictor of metastasis and survival in colorectal cancer. J Pathol. 2010; 220(4):475-89. DOI: 10.1002/path.2668. View

Shakir M, Gill J, Lundquist E . Interactions of UNC-34 Enabled with Rac GTPases and the NIK kinase MIG-15 in Caenorhabditis elegans axon pathfinding and neuronal migration. Genetics. 2005; 172(2):893-913. PMC: 1456253. DOI: 10.1534/genetics.105.046359. View

Joo K, Jin J, Kim E, Kim K, Kim Y, Kang B . MET signaling regulates glioblastoma stem cells. Cancer Res. 2012; 72(15):3828-38. DOI: 10.1158/0008-5472.CAN-11-3760. View

Li Y, Lal B, Kwon S, Fan X, Saldanha U, Reznik T . The scatter factor/hepatocyte growth factor: c-met pathway in human embryonal central nervous system tumor malignancy. Cancer Res. 2005; 65(20):9355-62. DOI: 10.1158/0008-5472.CAN-05-1946. View

Qiu M, Qian Y, Zhao X, Wang S, Feng X, Chen X . Expression and prognostic significance of MAP4K4 in lung adenocarcinoma. Pathol Res Pract. 2012; 208(9):541-8. DOI: 10.1016/j.prp.2012.06.001. View

Chapman J, Li H, Lundquist E . The MIG-15 NIK kinase acts cell-autonomously in neuroblast polarization and migration in C. elegans. Dev Biol. 2008; 324(2):245-57. PMC: 2642615. DOI: 10.1016/j.ydbio.2008.09.014. View

10.

Rodrigues G, Park M, Schlessinger J . Activation of the JNK pathway is essential for transformation by the Met oncogene. EMBO J. 1997; 16(10):2634-45. PMC: 1169874. DOI: 10.1093/emboj/16.10.2634. View

11.

Katoh Y, Katoh M . Hedgehog target genes: mechanisms of carcinogenesis induced by aberrant hedgehog signaling activation. Curr Mol Med. 2009; 9(7):873-86. DOI: 10.2174/156652409789105570. View

12.

Roussel M, Hatten M . Cerebellum development and medulloblastoma. Curr Top Dev Biol. 2011; 94:235-82. PMC: 3213765. DOI: 10.1016/B978-0-12-380916-2.00008-5. View

13.

Munshi N, Jeay S, Li Y, Chen C, France D, Ashwell M . ARQ 197, a novel and selective inhibitor of the human c-Met receptor tyrosine kinase with antitumor activity. Mol Cancer Ther. 2010; 9(6):1544-53. DOI: 10.1158/1535-7163.MCT-09-1173. View

14.

Sierra J, Tsao M . c-MET as a potential therapeutic target and biomarker in cancer. Ther Adv Med Oncol. 2011; 3(1 Suppl):S21-35. PMC: 3225018. DOI: 10.1177/1758834011422557. View

15.

Taylor M, Northcott P, Korshunov A, Remke M, Cho Y, Clifford S . Molecular subgroups of medulloblastoma: the current consensus. Acta Neuropathol. 2011; 123(4):465-72. PMC: 3306779. DOI: 10.1007/s00401-011-0922-z. View

16.

Collins C, Hong J, Sapinoso L, Zhou Y, Liu Z, Micklash K . A small interfering RNA screen for modulators of tumor cell motility identifies MAP4K4 as a promigratory kinase. Proc Natl Acad Sci U S A. 2006; 103(10):3775-80. PMC: 1383649. DOI: 10.1073/pnas.0600040103. View

17.

Snuderl M, Batista A, Kirkpatrick N, Ruiz de Almodovar C, Riedemann L, Walsh E . Targeting placental growth factor/neuropilin 1 pathway inhibits growth and spread of medulloblastoma. Cell. 2013; 152(5):1065-76. PMC: 3587980. DOI: 10.1016/j.cell.2013.01.036. View

18.

Zavarella S, Nakada M, Belverud S, Coniglio S, Chan A, Mittler M . Role of Rac1-regulated signaling in medulloblastoma invasion. Laboratory investigation. J Neurosurg Pediatr. 2009; 4(2):97-104. DOI: 10.3171/2009.4.PEDS08322. View

19.

Northcott P, Shih D, Peacock J, Garzia L, Morrissy A, Zichner T . Subgroup-specific structural variation across 1,000 medulloblastoma genomes. Nature. 2012; 488(7409):49-56. PMC: 3683624. DOI: 10.1038/nature11327. View

20.

Liu A, Cai J, Zhao X, Jiang T, He T, Fu H . ShRNA-targeted MAP4K4 inhibits hepatocellular carcinoma growth. Clin Cancer Res. 2011; 17(4):710-20. DOI: 10.1158/1078-0432.CCR-10-0331. View