Protein kinases are intensely studied mediators of cellular signaling, yet important questions remain regarding their regulation and in vivo properties. Here, we use a probe-based chemoprotemics platform to profile several well studied kinase inhibitors against >200 kinases in native cell proteomes and reveal biological targets for some of these inhibitors. Several striking differences were ide...

Focal adhesion kinase (FAK) is a major drug target in cancer and current inhibitors targeted to the ATP-binding pocket of the kinase domain have entered clinical trials. However, preliminary results have shown limited single-agent efficacy in patients. Despite these unfavorable data, the molecular mechanisms that drive intrinsic and acquired resistance to FAK-kinase inhibitors are largely unkno...

The potent natural toxins microcystin, nodularin, and okadaic acid act rapidly to induce apoptotic cell death. Here we show that the apoptosis correlates with protein phosphorylation events and can be blocked by protein kinase inhibitors directed against the multifunctional Ca /calmodulin-dependent protein kinase II (CaMKII). The inhibitors used comprised a battery of cell-permeable protein kin...

This study was undertaken to examine the surface expression and regulation of CD14 on human alveolar macrophages (HAM). HAM obtained by bronchoalveolar lavage were cultured with or without LPS and with or without fetal bovine serum (FBS) on plastic or Teflon surfaces. CD14 expression was assessed by immunofluorescence. The roles of protein tyrosine kinase, protein kinase A, and protein kinase C...

Transient receptor potential vanilloid 3 subtype (TRPV3) plays an important role in pruritus. From our previous work, chronic pruritus dominantly attenuated TRPV3 knockout mice (TRPV3 KO). We found functional coupled with protease-activated 2 (PAR2) keratinocytes inducing TSLP releasing atopic dermatitis (AD). With bioinformatics investigation, we that mast cells of KO infiltrated less the derm...

Protein kinases play critical roles in signal transduction pathways by transmitting extracellular signals across the cell membrane to distant locations in the cytoplasm and the nucleus. The development of protein kinase inhibitors has been hindered by the broad overlapping substrate specificities exhibited by these enzymes. The design of bisubstrate analog inhibitors could provide for the enhan...

Okadaic acid and microcystin-LR, both potent inhibitors of protein phosphatases (PP), blocked vesicle fusion in a cell-free system. The effect of okadaic acid was reversed by the purified catalytic subunit of PP2A, but not PP1. Inhibition was gradual, required Mg-ATP, and was reduced by protein kinase inhibitors, indicating that it was mediated via protein phosphorylation. A candidate protein k...

teins comprising 2 major subfamilies, the protein serine/threonine kinases and protein tyrosine kinases (PTKs). Protein kinases function as components of signal transduction pathways, playing a central role in diverse biological processes such as control of cell growth, metabolism, differentiation, and apoptosis. The development of selective protein kinase inhibitors that can block or modulate ...

Although breast cancer molecular subtypes have been extensively defined by means of gene expression profiling over the past decade, little is known, at the proteomic level, as to how signaling pathways are differentially activated and serve to control proliferation in different breast cancer subtypes. We used reverse-phase protein arrays to examine phosphorylation status of 100 proteins in a pa...

Heat shock protein 90 (Hsp90) is an adenosine triphosphate dependent molecular chaperone in eukaryotic cells that regulates the activation and maintenance of numerous regulatory and signaling proteins including epidermal growth factor receptor, human epidermal growth factor receptor 2, mesenchymal-epithelial transition factor, cyclin-dependent kinase-4, protein kinase B, hypoxia-inducible facto...