Integrins, cancer and snake toxins (mini-review)

Abstract

KEY WORDS: integrin, angiogenesis, cancer, apoptosis, snake toxin, snake venom C-type lectin, metalloprotease, disintegrin. CORRESPONDENCE TO:G. RÁDIS-BAPTISTA, Department of Biochemistry and Molecular Biology, Federal University of Ceará, Picí Campus, P.O. Box 6020, 60451-970, Fortaleza, Ceará, Brazil. Phone: +55 85 288 9817. Fax: +55 85 288 9789. Email: radisbra@ufc.br G. Rádis-Baptista INTEGRINS, CANCER AND SNAKE TOXINS (MINI-REVIEW). J. Venom. Anim. Toxins incl. Trop. Dis., 2005, 11, 3, p. 218 INTEGRINSIntegrins constitute a large family of focal adhesion proteins, in other words, transmembrane proteins of adhesion that keep cells attached to the extracellular matrix; the latter composed of an intricate network of proteins and polysaccharides on the cell surface (41). Integrins work as receptors for several types of cell matrix proteins, for example collagen, fibronectin, lamin, vitronectin, and fibrinogen (50).The integrins family comprises, in mammals, at least 24 members of heterodimeric transmembrane proteins, which are formed by the noncovalent association of two glycoproteins: one α subunit out of 19 and one β subunit from 9 types. The diversity of the integrins family is further increased not only by alternative mRNA splicing of some α and β subunits, but also by their post-translational modification (49,110). As example of integrin assembly, β 1 subunit associates with twelve subtypes of the α subunit. Thus, α1β1, α2β1, α3β1, α4β1, α5β1, α6β1, α7β1, α8β1, α9β1, α10β1, α11β1, and αvβ1 are found on almost all the vertebrate cells. In contrast, αv subunit, where v stands for vitronectin receptor, associates with more than one β subunit, making up αvβ1, αvβ3, αvβ5, αvβ6, and αvβ8. Multiple integrins recognize several cell matrix proteins, many of which usually contain the consensus motif of arginineglycine-aspartic acid (RGD). Extracellular divalent cations, such as Ca 2+ and Mg 2+ , influence the specificity and affinity of integrins binding to their ligands (8,102) In addition to participating in the cell matrix attachment, clustering of integrin at the sites of cell contact can activate intracellular signaling through focal adhesion kinase (FAK or pp125 FAK ) and via other associated proteins (18,97). FAK also associates with a number of other adapter, signaling, and cytoskeletal proteins, such as paxillin, Graf (GTPase regulator associated with FAK), cytohesin-1, Grb2, p130 CAS , α-actinin, filamin, and talin (17,92,97 On the other hand, Grb2 directly binding to FAK, in response to integrin activation, G. Rádis-Baptista INTEGRINS, CANCER AND SNAKE TOXINS (MINI-REVIEW). J. Venom. Anim. Toxins incl. Trop. Dis., 2005, 11, 3, p. 219 initiate Ras/Erk/MAP kinase pathway, and, consequently, cell proliferation in normal and pathological states (17,82,83,87). FAK is also implicated in controlling cell cycle progression via Jun NH2-terminal kinase (JNK) and preventing apoptosis through a pathway involving the proteins kinase C, phospholipase A2, and p53 (5, 76).Thus, the "outside-in" signaling medi...

Functional analysis of a recombinant PIII-SVMP, GST-acocostatin; an apoptotic inducer of HUVEC and HeLa, but not SK-Mel-28 cells

“…Integrin αvβ5 binds to vitronectin (Moschos et al, 2007), and its expression has been correlated with cancer aggressiveness of some invasive tumors (Radis-Baptista, 2005). Although the αvβ5 receptor recognizes the RGD motif (Barczyk et al, 2010), there are several peptides that lack RGD and bind to this receptor.…”

Isolation of an Anti–tumour Disintegrin: Dabmaurin–1, a Peptide Lebein–1–like, from Daboia mauritanica Venom

“…A partial Edman sequencing of 37 N-terminal residues of peptide P1, and a research inside database BLAST on Assembled Genomes [23], allowed us to find the close identity of P1 sequence with the N-terminal residues of a known disintegrin purified from Macrovipera lebetina venom, the alpha subunit of 64 residues of the heterodimer Lebein-1 ( Figure 2). Attribution of the unidentified residues X to half-cystines is consistent with an alignment of the P1 structure with those of Lebein-1α.…”

“…Remarkably, disintegrins, isolated from snake venoms bind integrins with high affinity and can durably block their interaction with ECM [19]. Therefore, in cancer treatment., venom disintegrins [3,[20][21][22][23] offer potential therapeutic alternatives to anti-tumour chemotherapeutic agents or may act in synergy with them as anti-angiogenic agents. By example, venom of king cobra Ophiophagus hannah was assessed to present strong anti-angiogenic effects in in vivo assays in yolk sac of zebrafish embryos [24].…”

A review on the Scorpaena plumieri fish venom and its bioactive compounds

“…And indeed, enzymatic activities are prominently described in the literature on fish — and terrestrial — venoms [40–43]. These enzymes initiate reactions that can contribute to local and systemic effects by acting as “spreading factors”, either increasing tissue permeability and facilitating the spread of other constituents of the venom or causing direct tissue damage to the prey [44].…”