BTK
小结
BTK是致癌基因，编码蛋白为Bruton的丙种球蛋白血症酪氨酸激酶，是一种细胞内激酶，在B细胞活化中起重要作用。B细胞受体（BCR）通过BCR相关的酪氨酸激酶（例如SYK和LYN）在质膜上磷酸化BTK达到激活BTK的目的。 BTK磷酸化的主要目标是磷脂酶C-γ2（PLCγ2），其导致下游信号传导途径的激活，包括NFAT，NFkB和MAPK途径。BTK信号传导还涉及淋巴细胞运输中的趋化因子受体信号传导和免疫应答中的Toll样受体信号传导。BTK的功能缺失性突变导致B细胞缺陷和免疫缺陷，称为X-连锁无丙种球蛋白血症（XLA），这种疾病导致骨髓中的前B细胞不能分化成成熟的循环B细胞。BTk的体细胞突变不常见，但是BTK信号转导对于B细胞源性恶性肿瘤的生长是至关重要的，如慢性淋巴细胞白血病（CLL）、套细胞淋巴瘤（MCL）、弥漫性大B细胞淋巴瘤（DLBCL）、多发性骨髓瘤（MM）和Waldenstrom巨球蛋白血症（WM）。BTK可在B细胞恶性肿瘤中过度表达。抑制BTK的信号通路已成为血液系统恶性肿瘤治疗的一种成功手段。
BTK (Bruton’s agammaglobulinemia tyrosine kinase) is a cytoplasmic tyrosine kinase that plays an important role in B-cell activation. The B-cell receptor (BCR) activates BTK when BCR-associated tyrosine kinases (such as SYK and LYN) phosphorylate BTK at the plasma membrane. The main target of BTK phosphorylation is phospholipase C-γ2 (PLCγ2) which leads to the activation of downstream signaling pathways including NFAT, NFkB and MAPK pathways. BTK signaling is also implicated in chemokine receptor signaling in lymphocyte trafficking and in Toll-like receptor signaling in the immune response. Loss-of-function mutations in BTK result in X-linked agammaglobulinemia (XLA), a disorder that results in the failure of pre-B cells in the bone marrow to differentiate into mature circulating B cells. While somatic mutations in BTK are not common, BTK signaling is critical for growth of B-cell derived malignancies such as chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), diffuse large B-cell lymphoma (DLBCL), multiple myeloma (MM) and Waldenstrom's Macroglobulinemia (WM). BTK is also overexpressed in B-cell malignancies. BTK inhibition has been a successful means of therapy in hematologic malignancies. The tyrosine kinase ibrutinib targets BTK and is FDA approved for the treatment of patients with MCL, CLL, and WM. However, acquired resistance to ibrutinib has been observed through mutations in BTK itself and in downstream effectors such as PLCγ2.