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KITENIN recruits Dishevelled/PKCδ to form a functional complex and controls the migration and invasiveness of colorectal cancer cells
  1. Dhong Hyo Kho (dhkoko89{at}empal.com)
  1. Chonnam National University Medical School, Korea, Republic of
    1. Jeong A Bae (bjounga{at}hotmail.com)
    1. Chonnam National University Medical School, Korea, Republic of
      1. Ji Hee Lee (leejh0707{at}empal.com)
      1. Chonnam National University Medical School, Korea, Republic of
        1. Hye Jung Cho (dalnim-1404{at}hanmail.net)
        1. Chonnam National University Medical School, Korea, Republic of
          1. Sang Hee Cho (sh115{at}chollian.net)
          1. Chonnam National University Medical School, Korea, Republic of
            1. Jae Hyuk Lee (jhlee{at}chonnam.ac.kr)
            1. Chonnam National University Medical School, Korea, Republic of
              1. Young-Woo Seo (whitefox{at}hanmail.net)
              1. Korea Basic Science Institute, Kwangju Center, Korea, Republic of
                1. Kyu Youn Ahn (kyahn{at}chonnam.ac.kr)
                1. Chonnam National University Medical School, Korea, Republic of
                  1. Ik Joo Chung (ijchung{at}chonnam.ac.kr)
                  1. Chonnam National University Medical School, Korea, Republic of
                    1. Kyung Keun Kim (kimkk{at}chonnam.ac.kr)
                    1. Chonnam National University Medical School, Korea, Republic of

                      Abstract

                      Background & Aims: KITENIN was previously reported to promote metastasis in mouse colon tumor models; however, the signaling mechanism of KITENIN at the cellular level was unknown. We investigated the functional role of KITENIN with respect to colorectal cancer (CRC) cell invasion and its expression in CRC tissues.

                      Methods: The effect of KITENIN on cell motility was analyzed in a migration and invasion assay upon its overexpression and knockdown. Immunoprecipitation was used to elucidate binding partners and immunohistochemistry was used to study expression levels.

                      Results: KITENIN overexpression enhanced the migration of rat intestinal epithelial cells, whereas a loss of invasiveness was observed in CRC cells after KITENIN-knockdown. Mechanically, KITENIN served as a scaffolding molecule that simultaneously recruited both Dishevelled (Dvl) and PKCδ_ through the membrane-spanning C-terminal region to form a complex that stimulated ERK/AP-1 via a PKCδ_ component but also organized the actin filament via a Dvl component. The KITENIN complex controlled the invasiveness of CRC cells etiologically harboring various mutations in APC, beta-catenin, or K-ras, in which AP-1 activation is redundant but the organization of the actin filament is indispensable for cell motility. Clinically, KITENIN expression was significantly higher in colon cancer tissues from advanced stage (III, IV) than that of stage I CRC and also in corresponding metastatic tissues.

                      Conclusions: The functional KITENIN complex acts as an executor in regard to cell motility and thereby controls CRC cell invasion, which may contribute to promoting metastasis.

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