What is the ‘Fork Initiation and Zipper’ model?
The ‘Fork Initiation and Zipper’ Model
Nectin-nectin cis interactions enable the formation of nectin-nectin trans interactions on apposing cells. These interactions, being uncooperative and short-lived in nature, are suited to the exploratory cell behavior initiated between cells coming into close contact [1].
Nectin-nectin trans interactions stimulate a signaling cascade (as reviewed in [2]) starting with the activation of the tyrosine kinase cellular-Src (c-Src) and leading to the activation of the Rho family GTPase Cdc42 via the Cdc42 GEF (guanine nucleotide exchange factor) FRG [3]. Activation of FRG requires the convergence of two phosphorylation pathways; one mediated by c-Src and one mediated by the small G protein Rap1, whose activation is itself a result of a c-Src pathway involving the Crk–C3G complex (an adaptor protein and a guanine nucleotide releasing protein, respectively) [4].
Cdc42 activation leads to increased filopodia formation and activation of the Rho family GTPase Rac that leads to increased lamellipodia formation. It should be noted that in this context Rac activation requires both Cdc42 and c-Src acting via the Rac GEF Vav2 [5]. The increase in filopodia enhances cell-cell contact, whilst the increase in lamellipodia promotes the closure of gaps between contact sites through increased cell surface receptor interactions [6]. These morphological events can therefore be described as ‘fork initiation’ (multiple filopodia extending outwards) and ‘zippering’ (lamellipodial protrusions sealing the gaps). This signaling cascade ultimately leads to the recruitment of cadherins to the nectin-based cell-cell contact in order to stabilize the formation of the adhesive junction (as reviewed in [7]).
Initial cell-cell contacts are mediated by nectin-nectin trans interactions that activate the Rho GTPase Cdc42. Cdc42 stimulates an increase in filopodial protrusions during a phase termed ‘fork initiation’. This promotes more trans interactions between nectins as well as cadherins. Further downstream signaling via Cdc42 activates Rac GTPase and leads to the ‘zipper’ phase, whereby lamellipodial protrusions seal the gaps between filopodial cell-cell contacts.
References
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- Takai Y, Miyoshi J, Ikeda W, and Ogita H. Nectins and nectin-like molecules: roles in contact inhibition of cell movement and proliferation. Nat. Rev. Mol. Cell Biol. 2008; 9(8):603-15. [PMID: 18648374]
- Fukuhara T, Shimizu K, Kawakatsu T, Fukuyama T, Minami Y, Honda T, Hoshino T, Yamada T, Ogita H, Okada M, and Takai Y. Activation of Cdc42 by trans interactions of the cell adhesion molecules nectins through c-Src and Cdc42-GEF FRG. J. Cell Biol. 2004; 166(3):393-405. [PMID: 15277544]
- Fukuyama T, Ogita H, Kawakatsu T, Fukuhara T, Yamada T, Sato T, Shimizu K, Nakamura T, Matsuda M, and Takai Y. Involvement of the c-Src-Crk-C3G-Rap1 signaling in the nectin-induced activation of Cdc42 and formation of adherens junctions. J. Biol. Chem. 2004; 280(1):815-25. [PMID: 15504743]
- Kawakatsu T, Ogita H, Fukuhara T, Fukuyama T, Minami Y, Shimizu K, and Takai Y. Vav2 as a Rac-GDP/GTP exchange factor responsible for the nectin-induced, c-Src- and Cdc42-mediated activation of Rac. J. Biol. Chem. 2004; 280(6):4940-7. [PMID: 15485841]
- Ehrlich JS, Hansen MDH, and Nelson WJ. Spatio-temporal regulation of Rac1 localization and lamellipodia dynamics during epithelial cell-cell adhesion. Dev. Cell 2002; 3(2):259-70. [PMID: 12194856]
- Irie K, Shimizu K, Sakisaka T, Ikeda W, and Takai Y. Roles and modes of action of nectins in cell-cell adhesion. Semin. Cell Dev. Biol. 2004; 15(6):643-56. [PMID: 15561584]
