Biochemical Studies of Systemic Lupus Erythematosus-Associated Mutations in Nonreceptor Tyrosine Kinases Ack1 and Brk.
Biochemical Studies of Systemic Lupus Erythematosus-Associated Mutations in Nonreceptor Tyrosine Kinases Ack1 and Brk.
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非受体酪氨酸激酶ACK1和BRK中与全身性红斑狼疮相关突变的生化研究。
DOI：
10.1021/acs.biochem.2c00685
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发表时间：
2023-03-21
期刊：
影响因子：
2.9
通讯作者：
Miller, W. Todd
中科院分区：
文献类型：
--
作者：
Kan, Yagmur;Paung, YiTing;Kim, Yunyoung;Seeliger, Markus A.;Miller, W. Todd
酪氨酸激酶（TKs）在调节细胞存活、迁移和增殖的信号传导过程中发挥重要作用。酪氨酸激酶的失调是许多疾病的基础，包括癌症、心血管疾病和发育疾病，以及免疫系统的病理。Ack1和Brk是非受体酪氨酸激酶（nrtk），以其在癌症中的作用而闻名。在这里，我们对系统性红斑狼疮（SLE）患者中发现的新的Ack1和Brk突变进行了生物化学表征。这些突变是nrtk中首次发现的sle1相关多态性。我们发现其中两个突变体的催化活性降低，而另外三个突变体的催化活性降低。为了了解与功能缺失表型相关的结构变化，我们解决了其中一个Ack1激酶突变体K161Q的晶体结构。此外，两个对催化活性至关重要的突变残基（ack1a156和K161）在其他tk中高度保守，它们在激酶家族其他成员中的替代可能与癌症有关。与在许多癌症中观察到的典型TKs功能获得突变相反，我们报告了Ack1和Brk的功能丧失突变，强调了TK参与人类疾病的复杂性。
Tyrosine kinases (TKs) play essential roles in signaling processes that regulate cell survival, migration, and proliferation. Dysregulation of tyrosine kinases underlies many disorders, including cancer, cardiovascular and developmental diseases, as well as pathologies of the immune system. Ack1 and Brk are nonreceptor tyrosine kinases (NRTKs) best known for their roles in cancer. Here, we have biochemically characterized novel Ack1 and Brk mutations identified in patients with systemic lupus erythematosus (SLE). These mutations are the first SLE-linked polymorphisms found among NRTKs. We show that two of the mutants are catalytically inactive, while the other three have reduced activity. To understand the structural changes associated with the loss-of-function phenotype, we solved the crystal structure of one of the Ack1 kinase mutants, K161Q. Furthermore, two of the mutated residues (Ack1 A156 and K161) critical for catalytic activity are highly conserved among other TKs, and their substitution in other members of the kinase family could have implications in cancer. In contrast to canonical gain-of-function mutations in TKs observed in many cancers, we report loss-of-function mutations in Ack1 and Brk, highlighting the complexity of TK involvement in human diseases.
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影响因子：
5.6
作者：
Guerois, R;Nielsen, JE;Serrano, L
通讯作者：
Serrano, L
DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
影响因子：
64.5
作者：
Azam, M;Latek, RR;Daley, GQ
通讯作者：
Daley, GQ
影响因子：
5.8
作者：
Chen, Jonathan E.;Huang, Conrad C.;Ferrin, Thomas E.
通讯作者：
Ferrin, Thomas E.
DOI：
10.1107/s0907444903006516
发表时间：
2003-05-01
影响因子：
2.2
作者：
Diederichs, K;McSweeney, S;Ravelli, RBG
通讯作者：
Ravelli, RBG