IndraLab

"Under conditions that reflect the kinetics of locostatin’s binding to RKIP and are not unduly stringent, locostatin abrogates the interaction of RKIP with Raf-1 and GRK2 ( xref and xref , and Ref. xref )."

"The phosphorylated RKIP interacts with GRK2 instead of RAF1, disrupting the function of GRK2, so it cannot inhibit the GPCR signaling pathway, allowing the signaling to continue and blocking the internalization of the receptor [ xref , xref ]."

"However, we reported that in addition to GRK2 and Raf-1 binding to PEBP1, the eicosanoid generating enzyme, 15LO1, also binds PEBP1. xref 15LO1, a lipoxygenase that generates 15 hydroxyeicosatetraenoic acid (15s-HETE), is upregulated in response to IL-13 stimulation of HAECs and is increased in asthma in relation to Type-2/eosinophilic processes. xref xref – xref , xref In addition to upregulation of 15LO1 in response to IL-13, stimulation of HAECs with IL-13 promotes binding of 15LO1 to PEBP1, with subsequent release of Raf-1, activation of ERK and increased expression of the airway mucin, MUC5AC. xref Thus, we hypothesized that in the presence of IL-13, 15LO1 would compete with GRK2 for binding to PEBP1, leading to more free GRK2 and greater likelihood for β2AR desensitization (even in the absence of β2 stimulation)."