Integrin-mediated adhesion regulates cellular responses to changes in the mechanical and biochemical properties of extracellular matrix. Cell–matrix caveolar endocytosis, dependent on caveolin 1 (Cav1) Tyr14 phosphorylation (pY14Cav1), control anchorage-dependent signaling. We find that cell–matrix pY14Cav1 levels mouse fibroblasts. Biochemical fractionation reveals endogenous be present caveol...

Notch signaling is important for tumor angiogenesis induced by vascular endothelial growth factor A. Blockade of the Notch ligand Dll4 inhibits tumor growth in a paradoxical way. Dll4 inhibition increases endothelial cell sprouting, but vessels show reduced perfusion. The reason for this lack of perfusion is not currently understood. Here we report that inhibition of Notch signaling in endothel...

UNLABELLED mTOR kinase inhibitors block mTORC1 and mTORC2 and thus do not cause the mTORC2 activation of AKT observed with rapamycin. We now show, however, that these drugs have a biphasic effect on AKT. Inhibition of mTORC2 leads to AKT serine 473 (S473) dephosphorylation and a rapid but transient inhibition of AKT T308 phosphorylation and AKT signaling. However, inhibition of mTOR kinase also...

A recent phase III trial of the MET kinase inhibitor cabozantinib in men with castration-resistant prostate cancer (CRPC) failed to meet its primary survival end point; however, most men with CRPC have intact androgen receptor (AR) signaling. As previous work supports negative regulation of MET by AR signaling, we hypothesized that intact AR signaling may have limited the efficacy of cabozantin...

BACKGROUND Plant development is exquisitely environmentally sensitive, with plant hormones acting as long-range signals that integrate developmental, genetic, and environmental inputs to regulate development. A good example of this is in the control of shoot branching, where wide variation in plant form can be generated in a single genotype in response to environmental and developmental cues. ...

AIMS In the heart, β1-adrenergic signaling involves cyclic adenosine monophosphate (cAMP) acting via both protein kinase-A (PKA) and exchange protein directly activated by cAMP (Epac): a guanine nucleotide exchange factor for the small GTPase Rap1. Inhibition of Epac-Rap1 signaling has been proposed as a therapeutic strategy for both cancer and cardiovascular disease. However, previous work sug...

Abstract Internalization and intracellular trafficking of G protein-coupled receptors (GPCRs) play pivotal roles in cell responsiveness. Dysregulation receptor can lead to aberrant signaling behavior. Here, using an endosomal BRET-based assay a high-throughput screen with the prototypical GPCR angiotensin II type 1 (AT1R), we sought identify inhibitors from library ~115,000 small molecules. We ...

In his pioneering work, Alan Turing showed that de novo pattern formation is possible if two substances interact that differ in their diffusion range. Since then, we have shown that pattern formation is possible if, and only if, a self-enhancing reaction is coupled with an antagonistic process of longer range. Knowing this crucial condition has enabled us to include nonlinear interactions, whic...

Abstract The potassium ion (K+) is vital for plant growth and development, K+-deprivation leads to reduced crop yields. Here we describe phenotypic, transcriptomic, mutant analyses investigate the signaling mechanisms mediating root architectural changes in Arabidopsis (Arabidopsis thaliana) Columbia. We showed effects on architecture are mediated through a reduction cell division lateral (LR) ...

Inhibition of VEGF signaling can promote lymph node metastasis in preclinical models, but the mechanism is not fully understood, and successful methods of prevention have not been found. Signaling of hepatocyte growth factor (HGF) and its receptor c-Met can promote the growth of lymphatics and metastasis of some tumors. We sought to explore the contributions of c-Met signaling to lymph node met...