The conserved scavenger receptor cysteine-rich superfamily in therapy and diagnosis.

The scavenger receptor cysteine-rich (SRCR) superfamily of soluble or membrane-bound protein receptors is characterized by the presence of one or several repeats of an ancient and highly conserved protein module, the SRCR domain. This superfamily (SRCR-SF) has been in constant and progressive expansion, now up to more than 30 members. The study of these members is attracting growing interest, which parallels that in innate immunity. No unifying function has been described to date for the SRCR domains, this being the result of the limited knowledge still available on the physiology of most members of the SRCR-SF, but also of the sequence versatility of the SRCR domains. Indeed, involvement of SRCR-SF members in quite different functions, such as pathogen recognition, modulation of the immune response, epithelial homeostasis, stem cell biology, and tumor development, have all been described. This has brought to us new information, unveiling the possibility that targeting or supplementing SRCR-SF proteins could result in diagnostic and/or therapeutic benefit for a number of physiologic and pathologic states. Recent research has provided structural and functional insight into these proteins, facilitating the development of means to modulate the activity of SRCR-SF members. Indeed, some of these approaches are already in use, paving the way for a more comprehensive use of SRCR-SF members in the clinic. The present review will illustrate some available evidence on the potential of well known and new members of the SRCR-SF in this regard.

Filamin B plays a key role in vascular endothelial growth factor-induced endothelial cell motility through its interaction with Rac-1 and Vav-2.

Actin-binding proteins filamin A (FLNA) and B (FLNB) are expressed in endothelial cells and play an essential role during vascular development. In order to investigate their role in adult endothelial cell function, we initially confirmed their expression pattern in different adult mouse tissues and cultured cell lines and found that FLNB expression is concentrated mainly in endothelial cells, whereas FLNA is more ubiquitously expressed. Functionally, small interfering RNA knockdown of endogenous FLNB in human umbilical vein endothelial cells inhibited vascular endothelial growth factor (VEGF)-induced in vitro angiogenesis by decreasing endothelial cell migration capacity, whereas FLNA ablation did not alter these parameters. Moreover, FLNB-depleted cells increased their substrate adhesion with more focal adhesions. The molecular mechanism underlying this effect implicates modulation of small GTP-binding protein Rac-1 localization and activity, with altered activation of its downstream effectors p21 protein Cdc42/Rac-activated kinase (PAK)-4/5/6 and its activating guanine nucleotide exchange factor Vav-2. Moreover, our results suggest the existence of a signaling complex, including FLNB, Rac-1, and Vav-2, under basal conditions that would further interact with VEGFR2 and integrin alphavbeta5 after VEGF stimulation. In conclusion, our results reveal a crucial role for FLNB in endothelial cell migration and in the angiogenic process in adult endothelial cells.