Bi-directional signaling by membrane-bound KitL induces proliferation and coordinates thymic endothelial cell and thymocyte expansion.
Bi-directional signaling by membrane-bound KitL induces proliferation and coordinates thymic endothelial cell and thymocyte expansion.
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通过膜结合的KitL双向信号诱导胸腺内皮细胞和胸腺细胞的增殖并协调其扩张。
DOI：
10.1038/s41467-018-07024-0
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发表时间：
2018-11-08
影响因子：
16.6
通讯作者：
Nerlov C
中科院分区：
文献类型：
--
作者：
Buono M;Thézénas ML;Ceroni A;Fischer R;Nerlov C
c-Kit受体的配体KitL以膜结合（mKitL）和可溶形式（sKitL）存在。尚未确定c-Kit激活以外的KitL功能。我们发现，共培养表达c-Kit和mKitL的NIH 3 T3细胞导致通过mKitL的信号传导：c-Kit结合的mKitL募集钙调节亲环蛋白配体（CAML）选择性激活Akt，导致CREB磷酸化，mTOR通路激活和细胞增殖增加。胸腺血管内皮细胞（VECs）中mKitL的激活诱导mKitL和Akt依赖性增殖，胸腺VECs中mKitL的基因消融阻断了新生儿胸腺扩增期间的c-Kit反应性和增殖。因此，mKitL-c-Kit形成双向信号传导复合物，其在发育中的胸腺中起作用以通过同时促进ETP存活和VEC增殖来协调胸腺VEC和早期胸腺祖细胞（ETP）扩增。这种机制可能与正常组织和依赖于KitL-c-Kit信号传导进行增殖的恶性肿瘤相关。已知c-Kit受体-Kit配体复合物信号传导激活c-Kit，并且对于组织发育是必需的。在此，Buono等人表明，膜结合的KitL信号传导通过CAML-Akt-CREB途径激活诱导增殖，确立了双向信号传导在组织扩张中的作用。
The ligand for the c-Kit receptor, KitL, exists as a membrane-associated (mKitL) and a soluble form (sKitL). KitL functions outside c-Kit activation have not been identified. We show that co-culture of c-Kit– and mKitL–expressing NIH3T3 cells results in signaling through mKitL: c-Kit–bound mKitL recruits calcium-modulating cyclophilin ligand (CAML) to selectively activate Akt, leading to CREB phosphorylation, mTOR pathway activation, and increased cell proliferation. Activation of mKitL in thymic vascular endothelial cells (VECs) induces mKitL- and Akt-dependent proliferation, and genetic ablation of mKitL in thymic VECs blocks their c-Kit responsiveness and proliferation during neonatal thymic expansion. Therefore, mKitL–c-Kit form a bi-directional signaling complex that acts in the developing thymus to coordinate thymic VEC and early thymic progenitor (ETP) expansion by simultaneously promoting ETP survival and VEC proliferation. This mechanism may be relevant to both normal tissues and malignant tumors that depend on KitL–c-Kit signaling for their proliferation. c-Kit receptor–Kit ligand complex signaling is known to activate c-Kit and is essential for tissue development. Here, Buono et al. show that membrane-bound KitL signaling induces proliferation via CAML-Akt-CREB pathway activation, establishing a role for bidirectional signaling in tissue expansion.
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影响因子：
7.2
作者：
Lisabeth EM;Falivelli G;Pasquale EB
通讯作者：
Pasquale EB
影响因子：
3.7
作者：
Chou SD;Prince T;Gong J;Calderwood SK
通讯作者：
Calderwood SK
影响因子：
64.8
作者：
Inra CN;Zhou BO;Acar M;Murphy MM;Richardson J;Zhao Z;Morrison SJ
通讯作者：
Morrison SJ
影响因子：
23.9
作者：
Medyouf, Hind;Mossner, Maximilian;Nowak, Daniel
通讯作者：
Nowak, Daniel
DOI：
10.1073/pnas.88.11.4671
发表时间：
1991-06-01
影响因子：
11.1
作者：
BRANNAN, CI;LYMAN, SD;COPELAND, NG
通讯作者：
COPELAND, NG