Okada Lab/Division of Cellular and Molecular Biology  Department of Oncogene Research

Cancer develops due to accumulation of mutations within a cell, which can then become malignant through immortalization and transformation. The malignant traits of cancer cells occur as they evade cancer inhibitory mechanisms such as apoptosis and senescence and acquire capacity for autonomous proliferation. In addition, cancer cells acquire invasive and metastatic characteristics through the loss of intercellular communication and altered cell morphology.

Src and cancer development

Src is a signaling molecule that localizes to the sub-membrane and was the first oncogene to be discovered. Normal tissues retain morphology by maintaining contact between neighboring cells via cell-cell junctions; however, cancer cells exhibit altered morphology (shown in Fig. 1) and undergo invasion and metastasis by secreting growth factors and proteases. Our laboratory has examined the role of Src as an activator of signaling pathways that control remodeling of the cytoskeleton, which contributes to motility by inducing morphological changes. In addition, Src is involved in cell membrane-mediated signaling pathways that promote expression of genes encoding proteases, thereby leading to malignancy. We aim to further elucidate the detailed molecular mechanisms by which Src affects cancer cell invasion and metastasis.

Interestingly, unlike other oncogenes, Src harbors no mutations. We found that Src is involved in a phenomenon called “cell competition,” in which cells interact and compete with each other, producing a “winner” based on their relative fitness. We anticipate that revealing the relationship between Src and cell competition will increase our understanding of the function of Src in cancer development; these studies are ongoing.

The molecular mechanism underlying  p18/Ragulator and mTOR nutrient signaling

mTOR is responsible for nutrition- and growth-related signaling in cells, and is involved in various biological phenomena. Our laboratory discovered that the p18 protein acts as an adaptor for molecules involved in regulating mTOR, and that it plays a crucial role in activating mTOR. We will continue our research into the molecular mechanism by which p18 regulates mTOR using protein structural analysis and by studying the molecular interactions between other factors involved
in mTOR regulation.
In addition, we are studying the molecular mechanisms underlying cancer defense in naked mole rats (NMR). NMR are rodents that are similar to mice; however, they are unique in that they have an exceptionally long life span (up to 10 times
that of mice). They also exhibit significant resistance to aging and cancer. Our laboratory focuses on identifying the molecular mechanisms that allow NMR to acquire these traits.

  • Fig.1. Protein Structure for Ragulator complex

  • Fig.2. Src activation induces morphological changes and increases cell mobility.

Staff

  • Prof. : Masato Okada
  • Assoc. Prof. : Shigeyuki Nada
  • Asst. Prof. : Kentarou Kajiwara
  • SA Asst. Prof. : Makoto Matsuda

Website

Publications

  • (1) Structural basis for the assembly of the Ragulator-Rag GTPase complex. Yonehara R., et al., Nature Commun (2017) 8:1625
    (2) Polarization of M2 macrophages requires Lamtor1 that integrates cytokine and amino-acid signals. Kimura T., et al Nat. Commun. (2016)7:13130
    (3) p18/LAMTOR1: a late endosome/lysosome-specific anchor protein for the mTORC1/MAPK signaling pathway. Nada S., et al., Methods Enzymol (2014) 535:249-63
    (4) The novel lipid raft adaptor p18 controls endosome dynamics by anchoring the MEK-ERK pathway to late endosomes. Nada S., et al., EMBO J. (2009) 28:477-89
    (5) The lipid raft-anchored adaptor protein cbp controls the oncogenic potential of c-Src. Oneyama C., et al., Mol Cell (2008) 30:426-36
    (6) Transmembrane phosphoprotein Cbp regulates the activities of Src-family tyrosine kinases. Kawabuchu M., et al., Nature (2000) 404:999-1003