IGF1R signaling drives antiestrogen resistance through PAK2/PIX activation in luminal breast cancer
ONCOGENE
Authors: Zhang, Yinghui; Wester, Lynn; He, Jichao; Geiger, Tamar; Moerkens, Marja; Siddappa, Ram; Helmijr, Jean A.; Timmermans, Mieke M.; Look, Maxime P.; van Deurzen, Caroline H. M.; Martens, John W. M.; Pont, Chantal; de Graauw, Marjo; Danen, Erik H. J.; Berns, Els M. J. J.; Meerman, John H. N.; Jansen, Maurice P. H. M.; van de Water, Bob
Abstract
Antiestrogen resistance in estrogen receptor positive (ER+) breast cancer is associated with increased expression and activity of insulin-like growth factor 1 receptor (IGF1R). Here, a kinome siRNA screen has identified 10 regulators of IGF1R-mediated antiestrogen with clinical significance. These include the tamoxifen resistance suppressors BMPR1B, CDK10, CDK5, EIF2AK1, and MAP2K5, and the tamoxifen resistance inducers CHEK1, PAK2, RPS6KC1, TTK, and TXK. The p21-activated kinase 2, PAK2, is the strongest resistance inducer. Silencing of the tamoxifen resistance inducing genes, particularly PAK2, attenuates IGF1R-mediated resistance to tamoxifen and fulvestrant. High expression of PAK2 in ER+ metastatic breast cancer patients is correlated with unfavorable outcome after first-line tamoxifen monotherapy. Phospho-proteomics has defined PAK2 and the PAK-interacting exchange factors PIX alpha/beta as downstream targets of IGF1R signaling, which are independent from PI3K/ATK and MAPK/ERK pathways. PAK2 and PIX alpha/beta modulate IGF1R signaling-driven cell scattering. Targeting PIX alpha/beta entirely mimics the effect of PAK2 silencing on antiestrogen re-sensitization. These data indicate PAK2/PIX as an effector pathway in IGF1R-mediated antiestrogen resistance.
Bruton tyrosine kinase (Btk) in X-linked agammaglobulinemia (XLA)
FRONTIERS IN BIOSCIENCE-LANDMARK
Authors: Vihinen, M; Mattsson, PT; Smith, CIE
Abstract
X-linked agammaglobulinemia (XLA) is a heritable immunodeficiency disorder that is caused by a differentiation block leading to almost complete absence of B lymphocytes and plasma cells. The affected protein is a cytoplasmic protein tyrosine kinase, Bruton's agammaglobulinemia tyrosine kinase (Btk). Btk along with Tec, Itk, Bmx and Txk belong to a distinct family of protein kinases. These proteins contain five regions; PH, TH, SH3, SH2 and kinase domains. Mutations causing XLA may affect any of these domains. About 380 unique mutations have been identified and are collected in a mutation database, BTKbase. Here, we describe the structure, function, and interactions of the affected signaling molecules in atomic detail.
COA
Publication 
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