Transmembrane interactions are needed for KAI1/CD82-mediated suppression of cancer invasion and metastasis

Rafijul Bari, Yanhui Zhang, Feng Zhang, Nick X. Wang, Christopher S. Stipp, Jie J. Zheng, Xin A. Zhang

Research output: Contribution to journalArticle

34 Citations (Scopus)

Abstract

In transmembrane (TM) domains, tetraspanin KAI1/CD82 contains an Asn, a Gln, and a Glu polar residue. A mutation of all three polar residues largely disrupts the migration-, invasion-, and metastasis-suppressive activities of KAI1/CD82. Notably, KAI1/CD82 inhibits the formation of microprotrusions and the release of microvesicles, while the mutation disrupts these inhibitions, revealing the connections of microprotrusion and microvesicle to KAI1/CD82 function. The TM polar residues are needed for proper interactions between KAI1/CD82 and tetraspanins CD9 and CD151, which also regulate cell movement, but not for the association between KAI1/CD82 and α3β1 integrin. However, KAI1/CD82 still efficiently inhibits cell migration when either CD9 or CD151 is absent. Hence, KAI1/CD82 interacts with tetraspanin and integrin by different mechanisms and is unlikely to inhibit cell migration through its associated proteins. Moreover, without significantly affecting the glycosylation, homodimerization, and global folding of KAI1/CD82, the TM interactions maintain the conformational stability of KAI1/CD82, evidenced by the facts that the mutant is more sensitive to denaturation and less associable with tetraspanins and supported by the modeling analysis. Thus, the TM interactions mediated by these polar residues determine a conformation either in or near the tightly packed TM region and this conformation and/or its change are needed for the intrinsic activity of KAI1/CD82. In contrast to immense efforts to block the signaling of cancer progression, the perturbation of TM interactions may open a new avenue to prevent cancer invasion and metastasis.

Original languageEnglish (US)
Pages (from-to)647-660
Number of pages14
JournalAmerican Journal of Pathology
Volume174
Issue number2
DOIs
StatePublished - Jan 1 2009

Fingerprint

Tetraspanins
Cell Movement
Neoplasm Metastasis
Integrins
Neoplasms
Mutation
Glycosylation
Proteins

All Science Journal Classification (ASJC) codes

  • Pathology and Forensic Medicine

Cite this

Transmembrane interactions are needed for KAI1/CD82-mediated suppression of cancer invasion and metastasis. / Bari, Rafijul; Zhang, Yanhui; Zhang, Feng; Wang, Nick X.; Stipp, Christopher S.; Zheng, Jie J.; Zhang, Xin A.

In: American Journal of Pathology, Vol. 174, No. 2, 01.01.2009, p. 647-660.

Research output: Contribution to journalArticle

Bari, Rafijul ; Zhang, Yanhui ; Zhang, Feng ; Wang, Nick X. ; Stipp, Christopher S. ; Zheng, Jie J. ; Zhang, Xin A. / Transmembrane interactions are needed for KAI1/CD82-mediated suppression of cancer invasion and metastasis. In: American Journal of Pathology. 2009 ; Vol. 174, No. 2. pp. 647-660.
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