GIV/Girdin, a nonreceptor GEF, directly links integrins to activation of trimeric G proteins to promote the acquisition of proinvasive traits in cancer cells.

In the course of our studies aiming to discover vascular bedspecific endothelial cell (EC) mitogens, we identified leukemia inhibitory factor (LIF) as a mitogen for bovine choroidal EC (BCE), although LIF has been mainly characterized as an EC growth inhibitor and an anti-angiogenic molecule. LIF stimulated growth of BCE while it inhibited, as previously reported, bovine aortic EC (BAE) growth. The JAK-STAT3 pathway mediated LIF actions in both BCE and BAE cells, but a caspase-independent proapoptotic signal mediated by cathepsins was triggered in BAE but not in BCE. LIF administration directly promoted activation of STAT3 and increased blood vessel density in mouse eyes. LIF also had protective effects on the choriocapillaris in a model of oxidative retinal injury. Analysis of available single-cell transcriptomic datasets shows strong expression of the specific LIF receptor in mouse and human choroidal EC. Our data suggest that LIF administration may be an innovative approach to prevent atrophy associated with AMD, through protection of the choriocapillaris.

Endothelial cells (ECs) form the inner lining of blood vessels and play crucial roles in angiogenesis. While it has been known for a long time that there are considerable differences among ECs from lymphatic and blood vessels, as well as among arteries, veins and capillaries, the full repertoire of endothelial diversity is only beginning to be elucidated. It has become apparent that the role of ECs is not just limited to their exchange functions. Indeed, a multitude of organ‐specific functions, including release of growth factors, regulation of immune functions, have been linked to ECs. Recent years have seen a surge into the identification of spatiotemporal molecular and functional heterogeneity of ECs, supported by technologies such as single‐cell RNA sequencing (scRNA‐seq), lineage tracing and intersectional genetics. Together, these techniques have spurred the generation of epigenomic, transcriptomic and proteomic signatures of ECs. It is now clear that ECs across organs and in different vascular beds, but even within the same vessel, have unique molecular identities and employ specialized molecular mechanisms to fulfil highly specialized needs. Here, we focus on the molecular heterogeneity of the endothelium in different organs and pathological conditions.

Signal transduction via both integrins and G protein‐coupled receptors (GPCRs) is critical to control cell behavior in health and disease. These two receptor classes have been traditionally believed to trigger distinct and independent signaling cascades. Here we report a novel mechanism of integrin signal transduction that requires activation of the trimeric G protein Gαi by the non‐receptor Guanine nucleotide Exchange Factor (GEF) GIV (aka Girdin), a pro‐metastatic protein. We demonstrate that GIV is necessary and sufficient to enhance responses to extracellular matrix (ECM) stimulation and make tumor cells more invasive. These responses include remodeling of the actin cytoskeleton and PI3K‐dependent signaling, resulting in enhanced haptotaxis and haptoinvasion. Tumor cells engineered to express GEF‐deficient GIV fail to transduce integrin signals into pro‐invasive cell responses. Mechanistically, we show that GIV and Gαi3 are recruited to integrin complexes upon ECM stimulation and activate a Gβγ‐PI3K‐Akt signaling cascade. In summary, our discoveries delineate a novel mechanism by which integrin signaling is rewired during metastasis to result in increased tumor invasiveness.This work is supported by the American Cancer society (RGS‐13‐362‐01‐TBE), the Elsa U. Pardee Foundation and NIH (R01GM108733).

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