The skin is a squamous epithelium that is continuously renewed by a population of basal layer stem/progenitor cells and can heal wounds. Here, we show that the transcription regulators YAP and TAZ localise to the nucleus in the basal layer of skin and are elevated upon wound healing. Skin-specific deletion of both YAP and TAZ in adult mice slows proliferation of basal layer cells, leads to hair loss and impairs regeneration after wounding. Contact with the basal extracellular matrix and consequent integrin-Src signalling is a key determinant of the nuclear localisation of YAP/TAZ in basal layer cells and in skin tumours. Contact with the basement membrane is lost in differentiating daughter cells, where YAP and TAZ become mostly cytoplasmic. In other types of squamous epithelia and squamous cell carcinomas, a similar control mechanism is present. By contrast, columnar epithelia differentiate an apical domain that recruits CRB3, Merlin (also known as NF2), KIBRA (also known as WWC1) and SAV1 to induce Hippo signalling and retain YAP/TAZ in the cytoplasm despite contact with the basal layer extracellular matrix. When columnar epithelial tumours lose their apical domain and become invasive, YAP/TAZ becomes nuclear and tumour growth becomes sensitive to the Src inhibitor Dasatinib.

Endothelial cells respond to vascular endothelial growth factor (VEGF) to produce new blood vessels. This process of angiogenesis makes a critical contribution during embryogenesis and also in the response to ischemia in adult tissues. We have studied the intracellular trafficking of the major VEGF receptor KDR (VEGFR2). Unlike other related growth factor receptors, we find that a significant proportion of KDR is held in an endosomal storage pool within endothelial cells. We find that KDR can be delivered to the plasma membrane from this intracellular pool and that VEGF stimulates this recycling to the cell surface. KDR recycling appears to be distinct from the previously characterized Rab4-and Rab11-dependent pathways, but, instead, KDR ؉ recycling vesicles contain Src tyrosine kinase and VEGFstimulated recycling requires Src activa- IntroductionAngiogenesis is the fundamental physiologic process by which new blood vessels are generated from preexisting vasculature. It plays a crucial role in embryogenesis, where it is required for elaboration of the vasculature from the primary vascular plexus. In normal adult physiology, angiogenesis is significant in a relatively limited number of processes-primarily in the formation of endometrial vessels in the uterus and development of the corpus luteum during the ovulation cycle. 1 Angiogenesis becomes more widely important to adult physiology through its critical involvement in a number of pathologic conditions. Active angiogenesis makes a positive contribution to the woundhealing process and also in the response to tissue ischemia-hypoxic tissues generate proangiogenic signals that stimulate the formation of new vessels and so improve perfusion. 2 Angiogenesis makes an unwanted contribution to the growth of solid tumors, with cancer cells secreting proangiogenic factors to provide a blood supply for the growing mass. 3 Deregulated angiogenesis is an underlying cause of proliferative diabetic retinopathy, a major vascular complication of both type I and type II diabetes, 4 and also contributes to other disease states such as age-related macular degeneration, rheumatoid arthritis, and psoriasis. 5,6 Understanding of the regulatory mechanisms of angiogenesis is hence seen not only as a fundamental problem in human biology but also as an important goal in medical research.Angiogenesis is controlled by a wide range of positive and negative signals. Vascular endothelial growth factor (VEGF) is the most critical and potent of the proangiogenic regulators 7-9 and is secreted by tissues in response to hypoxia or inflammation. 9 VEGF binds to VEGF receptors (VEGFRs) on the surface of endothelial cells, triggering a cascading series of signaling pathways that stimulate endothelial cell sprouting, migration, tube formation, proliferation, and survival. 10 There are 3 human members of the VEGFR family: VEGFR1/Flt-1, VEGFR2/Flk-1/KDR, and VEGFR3/Flt-4. 11 These proteins are members of the larger family of receptor tyrosine kinases (RTKs), which includes the plateletderived growth f...

Cancer cells can invade three-dimensional matrices by distinct mechanisms, recently defined by their dependence on extracellular proteases, including matrix metalloproteinases. Upon treatment with protease inhibitors, some tumour cells undergo a 'mesenchymal to amoeboid' transition that allows invasion in the absence of pericellular proteolysis and matrix degradation. We show here that in HT1080 cells, this transition is associated with weakened integrin-dependent adhesion, consistently reduced cell surface expression of the a2b1 integrin collagen receptor and impaired signalling downstream, as judged by reduced autophosphorylation of focal adhesion kinase (FAK). On examining cancer cells that use defined invasion strategies, we show that distinct from mesenchymal invasion, amoeboid invasion is independent of intracellular calpain 2 proteolytic activity that is usually needed for turnover of integrin-linked adhesions during two-dimensional planar migration. Moreover, an inhibitor of Rho/ROCK signalling, which specifically impairs amoeboid-like invasion, restores cell surface expression of a2b1 integrin, downstream FAK autophosphorylation and calpain 2 sensitivity -features of mesenchymal invasion. These findings link weakened integrin function to a lack of requirement for calpain 2-mediated integrin adhesion turnover during amoeboid invasion. In keeping with the need for integrin adhesion turnover, mesenchymal invasion is uniquely sensitive to Src inhibitors. Thus, the need for a major pathway that controls integrin adhesion turnover defines and distinguishes cancer cell invasion strategies.

The interaction of cells with surrounding matrix and neighbouring cells governs many aspects of cell behaviour. Aside from transmitting signals from the external environment, adhesion receptors also receive signals from the cell interior. Here we review the interrelationship between adhesion receptors, tyrosine kinases (both growth factor receptor and non-receptor) and modulators of the actin cytoskeletal network. Deregulation of many aspects of these signalling pathways in cancer highlights the need for a better understanding of the complexities involved.