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Figure 2. Function, structure, and expression of SOS-1 in human gingiva. (A) Schematic representation of the major intracellular signaling pathways regulated by SOS-1. In unstimulated cells, SOS-1 associates preferentially with the adaptor molecule Grb2. Binding of a growth factor to its receptor induces autophosphorylation of the growth factor receptor’s cytoplasmic tail. The SOS-1/Grb2 complex is translocated to the activated receptor, where it associates with Ras and promotes formation of GTP from GDP and activates Ras. Activated Ras induces phosphorylation of ERK1/2 of the mitogen-activated protein kinase (MAPK) pathway that regulates various key cell functions. The activated MAPK can phosphorylate SOS-1, leading to dissociation of the SOS-1/Grb2 complex (dashed lines). In the stimulated state, SOS-1 can also form a complex with the adaptor molecules E3b1 and Eps8 instead of Grb2. Formation of this trimolecular complex is not affected by phosphorylation of SOS-1 by the MAPK pathway. The trimolecular complex promotes association of SOS-1 with the small GTPase Rac and causes Rac activation by inducing nucleotide exchange from GDP to GTP. Activated Rac regulates re-organization of cytoskeletal actin and the cell functions that are regulated by this process. The activation of Ras by growth factors is usually short-lived, while the activation of Rac is sustained. (B) Structural comparison of the wild-type and mutant SOS-1 present in HGF1. SOS-1 is a multidomain protein. Together, the DH (Dbl homology) domain and the PH (pleckstrin homology) domain are involved in the activation of Rac. The Ras exchanger motif (Rem) domain and the Cdc25 domain are both needed for the interaction with Ras. The last C-terminal domain contains several proline-rich motifs that serve as a docking site for the src homology 3 (SH3) domain present in the adaptor molecules Grb2 and E3b1. In HGF1, there is a single cytosine insertion at codon 1083 (proline) in exon 21 that results in a frame-shift mutation and an early termination of the protein. The mutant protein also has a 22-amino-acid missense addition at the C-terminus. (C) Expression of SOS-1 in human gingiva. SOS-1 was immunolocalized in healthy human marginal gingiva with a polyclonal antibody against SOS-1 (Santa Cruz Biotechnology Inc., Santa Cruz, CA, USA), with the ABC avidin-peroxidase reagent (Vectastain Elite kit, Vector Laboratories Inc., Burlingame, CA, USA) and the VIP substrate (Vector Laboratories Inc.). SOS-1 localizes in the basal and spinous layers of the epithelium and in connective tissue cells (a). In the connective tissue, SOS-1 is expressed by blood vessels (arrowheads) and fibroblasts (arrows) (b). In the rete ridges of the epithelium, the strongest expression of SOS-1 localizes in the cytoplasm of the basal cells (c). In the connective tissue papilla area, the strongest immunoreactivity for SOS-1 localizes at the basal cell membrane, facing the basement membrane (d; arrowheads). A set of representative tissue sections from five different individuals is shown. E, epithelium; CT, connective tissue. Magnification bar = 50 µm.
J DENT RES, Vol. 86, No. 1,
25-34 (2007)
DOI: 10.1177/154405910708600104
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