Unraveling the Role of KIAA1199, a Novel Endoplasmic Reticulum Protein, in Cancer Cell Migration

Evensen, Nikki A.; Kuscu, Cem; Nguyen, Hoang-Lan; Zarrabi, Kevin; Dufour, Antoine; Kadam, Pournima; Hu, Youjun; Pulkoski‐Gross, Ashleigh; Bahou, Wadie F.; Zucker, Stanley; Cao, Jian

doi:10.1093/jnci/djt224

Cited by 110 publications

(158 citation statements)

References 38 publications

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“…Nevertheless, CEMIP has several features that are inconsistent with the notion that it is a hyaluronidase that functions in the extracellular space. For example, although CEMIP is a secreted protein with an N-terminal signal sequence (38), culture supernatants of CEMIP-transfected cells show little HA-degrading activity (16), and CEMIP is detected mainly intracellularly (16,17). Concerning the lack of activity in culture supernatant, Yoshida et al (16) reported that CEMIP-mediated HA degradation requires the participation of the clathrin-coated pit pathway, suggesting that CEMIP may function in intracellular compartments rather than in the extracellular space.…”

Section: Discussionmentioning

confidence: 99%

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A mammalian homolog of the zebrafish transmembrane protein 2 (TMEM2) is the long-sought-after cell-surface hyaluronidase

Yamamoto

Tobisawa

Inubushi

et al. 2017

Journal of Biological Chemistry

140

162

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Edited by Amanda J. Fosang Hyaluronan (HA) is an extremely large polysaccharide (glycosaminoglycan) involved in many cellular functions. HA catabolism is thought to involve the initial cleavage of extracellular high-molecular-weight (HMW) HA into intermediate-size HA by an extracellular or cell-surface hyaluronidase, internalization of intermediate-size HA, and complete degradation into monosaccharides in lysosomes. Despite considerable research, the identity of the hyaluronidase responsible for the initial HA cleavage in the extracellular space remains elusive. HYAL1 and HYAL2 have properties more consistent with lysosomal hyaluronidases, whereas CEMIP/KIAA1199, a recently identified HA-binding molecule that has HA-degrading activity, requires the participation of the clathrincoated pit pathway of live cells for HA degradation. Here we show that transmembrane protein 2 (TMEM2), a mammalian homolog of a protein playing a role in zebrafish endocardial cushion development, is a cell-surface hyaluronidase. Live immunostaining and surface biotinylation assays confirmed that mouse TMEM2 is expressed on the cell surface in a type II transmembrane topology. TMEM2 degraded HMW-HA into ϳ5-kDa fragments but did not cleave chondroitin sulfate or dermatan sulfate, indicating its specificity to HA. The hyaluronidase activity of TMEM2 was Ca 2؉ -dependent; the enzyme's pH optimum is around 6 -7, and unlike CEMIP/ KIAA1199, TMEM2 does not require the participation of live cells for its hyaluronidase activity. Moreover, TMEM2-expressing cells could eliminate HA immobilized on a glass surface in a contact-dependent manner. Together, these data suggest that TMEM2 is the long-sought-after hyaluronidase that cleaves extracellular HMW-HA into intermediate-size fragments before internalization and degradation in the lysosome.Hyaluronic acid (HA) 2 is a glycosaminoglycan composed of repeating disaccharide units of glucuronic acid and N-acetylglucosamine. It is a linear polymer of extremely large molecular mass, often exceeding 10 6 Da (1). The sheer size of HA suggests that cells should have very efficient mechanisms for its metabolism. In fact, one-third of the total body HA, which is estimated to be 15 g in a human with a 70-kg body weight, is thought to be turned over daily (2). In skin, the metabolic halflife of HA is 1 to 1.5 days (3). It is believed that high-molecularweight (HMW) HA (10 6 -10 7 Da) is first degraded extracellularly into intermediate-size fragments of 10 -100 kDa. These are then internalized and degraded to monosaccharides by the combined actions of lysosomal hyaluronidase and exoglucosidases (4). Considering the accumulating evidence for the role of HA degradation in tumor invasion and metastasis (5), identifying the molecule(s) that degrade HA on the cell surface is an important biological issue.The HYAL family molecules have been implicated as the major players in HA catabolism. HYAL1 and HYAL2 are expressed widely and postulated to be the key hyaluronidases involved in HA catabolism in somatic tissues. How...

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Section: Discussionmentioning

confidence: 99%

“…Also noteworthy is that neither conditioned media of CEMIP-expressing cells nor recombinant CEMIP show HA-degrading activity. In addition, CEMIP is detected mainly inside the cells (16,17).…”

Section: Hyaluronic Acid (Ha)mentioning

confidence: 99%

A mammalian homolog of the zebrafish transmembrane protein 2 (TMEM2) is the long-sought-after cell-surface hyaluronidase

Yamamoto

Tobisawa

Inubushi

et al. 2017

Journal of Biological Chemistry

140

162

View full text Add to dashboard Cite

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“…For example, KIAA1199 was significantly downregulated by B-Raf or MEK inhibition. KIAA1199 emerges as a marker of poor prognosis in several tumor entities, including colorectal carcinoma, but has never been linked to BRAF mutations before (39,40,55). Its activity as a promoter of cell migration in noncolorectal carcinoma cell lines (55) fits well to the strong reduction of invasive behavior of Colo-205 cells with inhibition or knockdown of B-Raf V600E .…”

Section: V600ementioning

confidence: 97%

B-Raf Inhibitors Induce Epithelial Differentiation inBRAF-Mutant Colorectal Cancer Cells

et al. 2015

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BRAF mutations are associated with aggressive, less-differentiated and therapy-resistant colorectal carcinoma. However, the underlying mechanisms for these correlations remain unknown. To understand how oncogenic B-Raf contributes to carcinogenesis, in particular to aspects other than cellular proliferation and survival, we generated three isogenic human colorectal carcinoma cell line models in which we can dynamically modulate the expression of the B-Raf V600E oncoprotein. Doxycyclin-inducible knockdown of endogenous B-Raf V600E decreases cellular motility and invasion in conventional and three-dimensional (3D) culture, whereas it promotes cell-cell contacts and induces various hallmarks of differentiated epithelia. Importantly, all these effects are recapitulated by B-Raf (PLX4720, vemurafenib, and dabrafenib) or MEK inhibitors (trametinib). Surprisingly, loss of B-Raf V600E in HT29 xenografts does not only stall tumor growth, but also induces glandular structures with marked expression of CDX2, a tumor-suppressor and master transcription factor of intestinal differentiation. By performing the first transcriptome profiles of PLX4720-treated 3D cultures of HT29 and Colo-205 cells, we identify several upregulated genes linked to epithelial differentiation and effector functions, such as claudin-1, a Cdx-2 target gene encoding a critical tight junction component. Thereby, we provide a mechanism for the clinically observed correlation between mutant BRAF and the loss of Cdx-2 and claudin-1. PLX4720 also suppressed several metastasis-associated transcripts that have not been implicated as targets, effectors or potential biomarkers of oncogenic B-Raf signaling so far. Together, we identify a novel facet of clinically applied B-Raf or MEK inhibitors by showing that they promote cellular adhesion and differentiation of colorectal carcinoma cells.

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“…Silencing a novel endoplasmic reticulum protein KIAA1199 discovered earlier to induce cell migration in invasive cancers caused a reduction of 75% in cell migration and 80% in cell invasion [35]. Another KKU-M213 exosome protein, CD147, was reported to play important roles in hepatocellular carcinoma invasion and metastasis [36].…”

Section: Accepted Manuscriptmentioning

confidence: 99%

Proteomics profiling of cholangiocarcinoma exosomes: A potential role of oncogenic protein transferring in cancer progression

Dutta

Reamtong

Panvongsa

et al. 2015

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Cholangiocarcinoma (CCA), a common primary malignant tumor of bile duct epithelia, is highly prevalent in Asian countries and unresponsive to chemotherapeutic drugs. Thus, a newly recognized biological entity for early diagnosis and treatment is highly needed. Exosomes are small membrane bound vesicles found in body fluids and released by most cell types including cancer cells. The vesicles contain specific subset of proteins and nucleic acids corresponding to cell types and play essential roles in pathophysiological processes. The present study aimed to assess the protein profiles of CCA-derived exosomes and their potential roles. We have isolated exosomes from CCA cells namely KKU-M213 and KKU-100 derived from Thai patients and their roles were investigated by incubation with normal human cholangiocyte (H69) cells. Exosomes were internalized into H69 cells and had no effects on viability or proliferation of the host cells. Interestingly, the exosomes from KKU-M213 cells only induced migration and invasion of H69 cells. Proteomic analysis of the exosomes from KKU-M213 cells disclosed multiple cancer related proteins that are not present in H69 exosomes. Consistent with the protein profile, treatment with KKU-M213 exosomes induced β-catenin and reduced E-cadherin expressions in H69 cells. Collectively, our results suggest that a direct cell-to-cell transfer of oncogenic proteins via exosomal pathway may be a novel mechanism for CCA progression and metastasis.

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Unraveling the Role of KIAA1199, a Novel Endoplasmic Reticulum Protein, in Cancer Cell Migration

Abstract: KIAA1199 serves as a novel cell migration-promoting gene and plays a critical role in maintaining cancer mesenchymal status.

Cited by 110 publications

References 38 publications

A mammalian homolog of the zebrafish transmembrane protein 2 (TMEM2) is the long-sought-after cell-surface hyaluronidase

A mammalian homolog of the zebrafish transmembrane protein 2 (TMEM2) is the long-sought-after cell-surface hyaluronidase

B-Raf Inhibitors Induce Epithelial Differentiation inBRAF-Mutant Colorectal Cancer Cells

Proteomics profiling of cholangiocarcinoma exosomes: A potential role of oncogenic protein transferring in cancer progression

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