Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 295, Issue 27, Pages 8972-8987Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.RA120.012835
Keywords
cargo sorting; coat protein complex II (COPII); planar cell polarity proteins; secretory transport pathway; Frizzled class receptor 6 (FZD6); transmembrane signaling; secretion-associated Ras-related GTPase 1A (SAR1A); cadherin EGF LAG seven-pass G-type receptor 1 (CELSR1); polybasic motif; trafficking; protein sorting; endoplasmic reticulum (ER); Golgi; vesicles
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Funding
- National Natural Science Foundation of China [NSFC 31871421]
- Shenzhen Science and Technology Innovation Committee [JCYJ20180306174847511]
- Hong Kong Research Grants Council [26100315, 16101116, 16102218, 16103319, AoE/M-05/12-3, C4002-17G, C4012-16E]
- Hong Kong Branch of Southern Marine Science and Engineering Guangdong Laboratory (Guangzhou) [SMSEGL20SC01]
- RGC of HK [C4002-17G, C4012-16E, AoE/M-05/12]
- Hong Kong Research Grants Council, University Grants Committee [GRF116150016, 16104018]
- Shenzhen Science and Technology Innovation Commission [JCYJ20170306161537148, JCYJ20180223181229868]
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Planar cell polarity (PCP) is a process during which cells are polarized along the plane of the epithelium and is regulated by several transmembrane signaling proteins. After their synthesis, these PCP proteins are delivered along the secretory transport pathway to the plasma membrane, where they perform their physiological functions. However, the molecular mechanisms that regulate PCP protein transport remain largely unclear. Here, we found that the delivery of a PCP protein, Frizzled-6, to the cell surface is regulated by two conserved polybasic motifs: one located in its first intracellular loop and the other in its C-terminal cytosolic domain. We observed that the polybasic motif of Frizzled is also important for its surface localization in theDrosophilawing. Results from a mechanistic analysis indicated that Frizzled-6 packaging into vesicles at the endoplasmic reticulum (ER) is regulated by a direct interaction between the polybasic motif and the Glu-62 and Glu-63 residues on the secretion-associated Ras-related GTPase 1A (SAR1A) subunit of coat protein complex II (COPII). Moreover, we found that newly synthesized Frizzled-6 is associated with another PCP protein, cadherin EGF LAG seven-pass G-type receptor 1 (CELSR1), in the secretory transport pathway, and that this association regulates their surface delivery. Our results reveal insights into the molecular machinery that regulates the ER export of Frizzled-6. They also suggest that the association of CELSR1 with Frizzled-6 is important, enabling efficient Frizzled-6 delivery to the cell surface, providing a quality control mechanism that ensures the appropriate stoichiometry of these two PCP proteins at cell boundaries.
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