Palmitoylation by DHHC3 is critical for the function, expression, and stability of integrin alpha6beta4.
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Sharma C, Rabinovitz I, Hemler ME
Palmitoylation by DHHC3 is critical for the function, expression, and stability of integrin alpha6beta4.
Cell Mol Life Sci. 2012 Jul;69(13):2233-44. doi: 10.1007/s00018-012-0924-6.
- PubMed ID
- 22314500 [ View in PubMed]
- Abstract
The laminin-binding integrin alpha6beta4 plays key roles in both normal epithelial and endothelial cells and during tumor cell progression, metastasis, and angiogenesis. Previous cysteine mutagenesis studies have suggested that palmitoylation of alpha6beta4 protein supports a few integrin-dependent functions and molecular associations. Here we took another approach and obtained strikingly different results. We used overexpression and RNAi knockdown in multiple cell types to identify protein acyl transferase DHHC3 as the enzyme responsible for integrin beta4 and alpha6 palmitoylation. Ablation of DHHC3 markedly diminished integrin-dependent cellular cable formation on Matrigel, integrin signaling through Src, and beta4 phosphorylation on key diagnostic amino acids (S1356 and 1424). However, unexpectedly, and in sharp contrast to prior alpha6beta4 mutagenesis results, knockdown of DHHC3 accelerated the degradation of alpha6beta4, likely due to an increase in endosomal exposure to cathepsin D. When proteolytic degradation was inhibited (by Pepstatin A), rescued alpha6beta4 accumulated intracellularly, but was unable to reach the cell surface. DHHC3 ablation effects were strongly selective for alpha6beta4. Cell-surface levels of ~10 other proteins (including alpha3beta1) were not diminished, and the appearance of hundreds of other palmitoylated proteins was not altered. Results obtained here demonstrate a new substrate for the DHHC3 enzyme and provide novel opportunities for modulating alpha6beta4 expression, distribution, and function.