Tenascin-C-Derived Peptide, TNIIIA2: Comparison
Please note this is a comparison between Version 1 by Motomichi Fujita and Version 4 by Nora Tang.

Matricellular proteins harbor functional sites within their molecular structures. These functional sites are released via proteolytic cleavage by inflammatory proteinases, and the peptides containing these hidden functional sites have unique biological activities that are often not detected in the parent molecules. A peptide containing the functional site of tenascin-C (TNC), termed TNIIIA2, which is highly released at sites of inflammation and in the tumor microenvironment, has the ability to potently and persistently activate β1-integrins. Based on these activities, TNIIIA2-containing TNC fragments/peptides are involved in the acquisition of aggressiveness in cancer progression.

  • Tenascin-C
  • TNIIIA2
  • β1-integrin
  • integrin activation
  • matricellular protein
  • platelet-derived growth factor
  • matricryptic site
  • matricryptin

1. Instructions

Tenascin-C (TNC) is a multifunctional glycoprotein that belongs to a family of matricellular proteins

Tenascin-C (TNC) is a multifunctional glycoprotein that belongs to a family of matricellular proteins

[1]

. It is highly expressed during embryonic development, but its expression levels rapidly decrease and are limited in normal adult tissues

[1]

. TNC is strongly re-expressed in particular environments such as inflammatory regions

[2]

, tissue remodeling

[3][4][5]

, and the tumor microenvironment (TME)

[6]

, indicating a close association with pathogenesis. A high expression of TNC has been observed in various cancers including pancreatic cancer

[7]

, gastric cancer

[8]

, colorectal cancer

[9]

, esophageal adenocarcinoma

[10]

, lung cancer

[11]

, breast cancer

[12]

, and glioma/glioblastoma

[6][13]

. High TNC levels are correlated with poor prognosis in patients with various types of cancer, and its expression is therefore considered a poor prognostic factor. Besides cancer cells, other cells in the TME including fibroblasts, endothelial cells, and macrophages express TNC, thus contributing to cancer aggression

[14][15].

.

2. Development

TNC has been shown to have both proadhesive and antiadhesive properties in a context-dependent manner

TNC has been shown to have both proadhesive and antiadhesive properties in a context-dependent manner

[1]

. These underlying mechanisms remain elusive but could be explained in terms of the considerable diversity of TNC’s molecular forms. As shown in 

Figure 1

A, TNC is composed of a central domain (assembly domain), epidermal growth factor (EGF)-like repeats, fibronectin (FN) type III-like domains, and a fibrinogen globe-like domain, which are capable of interaction with extracellular matrix (ECM) proteins, soluble factors, and cell receptors

[6]

. Moreover, human TNC contains 9 alternative splicing repeats in FN type III-like domains, and alternative splicing theoretically generates 511 possible splice variants

[1]

, thus leading to the expression of TNC’s multifunctional activities in a context-dependent manner

[6]

. ECM remodeling often occurs in the TME and inflammatory regions where bioactive functions are released via cleavage by inflammatory proteinases

[16]

. TNC can also be proteolytically processed by matrix metalloproteinases (MMP) a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS), and alternative splicing repeats within FN type III repeats are particularly cleaved by MMP, which in turn exposes the specific bioactivity of TNC

[1][16]

. Among the TNC variants, those containing the FN type III repeats A2 are highly expressed in malignancies

[17]

. Saito et al. previously found that FN type III repeats A2 of TNC molecules have cryptic sites composed of the amino acid sequence YTITIRGV (

Figure 1

A). Moreover, the 22-mer peptide TNIIIA2 containing its functional sites can induce the activation of integrin α5β1 through a lateral association with transmembrane heparan sulfate proteoglycan syndecan-4 (

Figure 1

B,C), which leads to the induction and potentiation of cell adhesion to the ECM

[18]

. This TNIIIA2-induced integrin activation is more potent and persistent than other known integrin activators

[19]

. Based on these effects, peptide TNIIIA2 was shown to influence various cellular functions

[20][21][22][23][24][25][26][27][28]

. Among them, the action of TNIIIA2 on survival and proliferation in stromal cells are interesting with regard to involvement in cancer progression. Peptide TNIIIA2 rendered NIH3T3 mouse nontransformed fibroblasts anoikis-resistant through integrin α5β1 activation-mediated prosurvival signaling

[19]

. Peptide TNIIIA2 also induced the platelet-derived growth factor (PDGF)-dependent dimerization of PDGF receptor (PDGF-R)β via the activation of integrin α5β1 to promote the PDGF-Rβ/Ras/mitogen-activated protein kinase (MAPK) signaling pathway, followed by the induction of hyperproliferation and the formation of dense multilayered cell aggregates—that is, transformed foci in NIH3T3 cells (

Figure 2

)

[19]

. These results suggest that TNIIIA2 has the ability to disrupt the normal cell phenotype. This raises the possibility that TNIIIA2-containing TNC fragments/peptides might be involved in oncogenic transformation and malignant progression

[24][25][26][27][28].

.

Figure 1.

 Tenascin-C (TNC)-derived TNIIIA2 fragments/peptides. (

A

) Schematic illustration of TNC and amino acid sequence of proadhesive peptide TNIIIA2. (

B

) Conformational shift of integrin activation by peptide TNIIIA2. (

C) Lateral interaction of integrin with syndecan-4 ectodomain by peptide TNIIIA2.

) Lateral interaction of integrin with syndecan-4 ectodomain by peptide TNIIIA2.

Figure 2. Physical and functional association between TNIIIA2-stimulated integrin α5β1 and PDGF receptor (PDGF-R). Peptide TNIIIA2 induces integrin α5β1 activation through a lateral association with syndecan-4, facilitating the formation of a molecular complex that includes activated integrin α5β1, syndecan-4, and activated PDGF-R in cholesterol- and caveolin-enriched membrane microdomains, which results in an enhanced activation of PDGF-R and leads to the hyperstimulation of cell proliferation.

 Physical and functional association between TNIIIA2-stimulated integrin α5β1 and PDGF receptor (PDGF-R). Peptide TNIIIA2 induces integrin α5β1 activation through a lateral association with syndecan-4, facilitating the formation of a molecular complex that includes activated integrin α5β1, syndecan-4, and activated PDGF-R in cholesterol- and caveolin-enriched membrane microdomains, which results in an enhanced activation of PDGF-R and leads to the hyperstimulation of cell proliferation.

References

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  20. Rika Tanaka; Toshiyuki Owaki; Sadahiro Kamiya; Takuya Matsunaga; Kazuya Shimoda; Hiroaki Kodama; Ryo Hayashi; Takashi Abe; Yosei P. Harada; Motoyuki Shimonaka; et al.Hirofumi YajimaHiroshi TeradaFumio Fukai VLA-5-mediated Adhesion to Fibronectin Accelerates Hemin-stimulated Erythroid Differentiation of K562 Cells through Induction of VLA-4 Expression. Journal of Biological Chemistry 2009, 284, 19817-19825, 10.1074/jbc.m109.009860.
  21. Yohei Saito; Toshiyuki Owaki; Takuya Matsunaga; Mizue Saze; Shogo Miura; Mao Maeda; Mayu Eguchi; Rika Tanaka; Junichi Taira; Hiroaki Kodama; et al.Sumio GotoYoshiroh NiitsuHiroshi TeradaFumio Fukai Apoptotic Death of Hematopoietic Tumor Cells through Potentiated and Sustained Adhesion to Fibronectin via VLA-4. Journal of Biological Chemistry 2009, 285, 7006-7015, 10.1074/jbc.m109.027581.
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  23. Kazuki Otsuka; Manabu Sasada; Y U Hirano; Yusuke Nohara; Takuya Iyoda; Yoshikazu Higami; Hiroaki Kodama; Fumio Fukai; Acyclic Retinoid Combined With Tenascin-C-derived Peptide Reduces the Malignant Phenotype of Neuroblastoma Cells Through N-Myc Degradation.. Anticancer Research 2019, 39, 3487-3492, 10.21873/anticanres.13494.
  24. Motomichi Fujita; Tetsuya Yamamoto; Takuya Iyoda; Tatsuya Fujisawa; Manabu Sasada; Reo Nagai; Chikako Kudo; Kazuki Otsuka; Sadahiro Kamiya; Hiroaki Kodama; et al.Fumio Fukai Aggressive Progression in Glioblastoma Cells through Potentiated Activation of Integrin α5β1 by the Tenascin-C-Derived Peptide TNIIIA2.. Molecular Cancer Therapeutics 2019, 18, 1649-1658, 10.1158/1535-7163.MCT-18-1251.
  25. Motomichi Fujita; Tetsuya Yamamoto; Takuya Iyoda; Tatsuya Fujisawa; Reo Nagai; Chikako Kudo; Manabu Sasada; Hiroaki Kodama; Fumio Fukai; Autocrine Production of PDGF Stimulated by the Tenascin-C-Derived Peptide TNIIIA2 Induces Hyper-Proliferation in Glioblastoma Cells.. International Journal of Molecular Sciences 2019, 20, 3183, 10.3390/ijms20133183.
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  27. Hideo Suzuki; Manabu Sasada; Sadahiro Kamiya; Yuka Ito; Hikaru Watanabe; Yuko Okada; Kazuma Ishibashi; Takuya Iyoda; Akinori Yanaka; Fumio Fukai; et al. The Promoting Effect of the Extracellular Matrix Peptide TNIIIA2 Derived from Tenascin-C in Colon Cancer Cell Infiltration. International Journal of Molecular Sciences 2017, 18, 181, 10.3390/ijms18010181.
  28. Motomichi Fujita; Manabu Sasada; Takuya Iyoda; Fumio Fukai; Involvement of Integrin-Activating Peptides Derived from Tenascin-C in Cancer Aggression and New Anticancer Strategy Using the Fibronectin-Derived Integrin-Inactivating Peptide. Molecules 2020, 25, 3239, 10.3390/molecules25143239.
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