Differential functions of phospholipid binding and palmitoylation of tumour suppressor EWI2/PGRL

Bo He, Yanhui Zhang, Mekel M. Richardson, Julian S. Zhang, Eric Rubinstein, Xin A. Zhang

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

The tumour suppressor EWI2 associates with tetraspanins and regulates tumour cell movement and proliferation. The short cytoplasmic domain of EWI2 is positively charged; five out of the ten residues of this domain are basic. In the present study we demonstrated that the EWI2 cytoplasmic tail interacts specifically with negatively charged PIPs (phosphatidylinositol phosphates), but not with other membrane lipids. The PIPs that interact with EWI2 cytoplasmic tail include PtdIns5P, PtdIns4P, PtdIns3P, PtdIns(3,5)P 2 and PtdIns(3,4)P 2. The binding affinity of PIPs to the EWI2 tail, however, is not solely based on charge because PtdIns5P, PtdIns4P and PtdIns3P have a higher affinity to EWI2 than PtdIns(3,5)P 2 and PtdIns(3,4)P 2 do. Mutation of either of two basic residue clusters in the EWI2 cytoplasmic tail abolishes PIP binding, and PIP binding is also determined by the position of basic residues in the EWI2 cytoplasmic tail. In addition, EWI2 is constitutively palmitoylated at the cytoplasmic cysteine residues located at the N-terminal of those basic residues. The PIP interaction is not required for, but appears to regulate, the palmitoylation, whereas palmitoylation is neither required for nor regulates the PIP interaction. Functionally, the PIP interaction regulates the stability of EWI2 proteins, whereas palmitoylation is needed for tetraspanin-EWI2 association and EWI2-dependent inhibition of cell migration and lamellipodia formation. For cell-cell adhesion and cell proliferation, the PIP interaction functions in opposition to the palmitoylation. In conclusion, the EWI2 cytoplasmic tail actively engages with the cell membrane via PIP binding and palmitoylation, which play differential roles in EWI2 functions.

Original languageEnglish (US)
Pages (from-to)399-411
Number of pages13
JournalBiochemical Journal
Volume437
Issue number3
DOIs
StatePublished - Aug 1 2011

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Lipoylation
Phosphatidylinositol Phosphates
Tumors
Phospholipids
Neoplasms
Phosphatidylinositols
Tetraspanins
Cells
Cell Proliferation
Cell Migration Inhibition
Pseudopodia
Protein Stability
Cell adhesion
Cell proliferation
Cell membranes
Membrane Lipids
Cell Adhesion
Cell Movement
Cysteine
Cell Membrane

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Differential functions of phospholipid binding and palmitoylation of tumour suppressor EWI2/PGRL. / He, Bo; Zhang, Yanhui; Richardson, Mekel M.; Zhang, Julian S.; Rubinstein, Eric; Zhang, Xin A.

In: Biochemical Journal, Vol. 437, No. 3, 01.08.2011, p. 399-411.

Research output: Contribution to journalArticle

He, Bo ; Zhang, Yanhui ; Richardson, Mekel M. ; Zhang, Julian S. ; Rubinstein, Eric ; Zhang, Xin A. / Differential functions of phospholipid binding and palmitoylation of tumour suppressor EWI2/PGRL. In: Biochemical Journal. 2011 ; Vol. 437, No. 3. pp. 399-411.
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