Department of Biochemistry and Molecular Biophysics, Howard Hughes Medical Institute, Institute for Cancer Genetics, USA.
Proc Natl Acad Sci U S A. 2010 Mar 30;107(13):5907-12. doi: 10.1073/pnas.1001647107. Epub 2010 Mar 10.
The cytosolic domain of Notch is a membrane-tethered transcription factor. Ligand binding ultimately leads to gamma-secretase cleavage within the transmembrane domain, allowing the intracellular domain to translocate to the nucleus and activate target gene transcription. Constitutive Notch signaling has been associated with human cancers such as T cell acute lymphoblastic leukemia (T-ALL). As tetraspanins have been implicated in many different signaling processes, we assessed their potential contribution to Notch signaling. We used a genetic assay in Caenorhabditis elegans to identify TSP-12 as a positive factor for Notch activity in several cellular contexts. Then, using a cell culture system, we showed that two human TSP-12 orthologs, TSPAN33 and TSPAN5, promote Notch activity and are likely to act at the gamma-secretase cleavage step. We also acquired evidence for functional redundancy among tetraspanins in both C. elegans and human cells. Selective inhibition of tetraspanins may constitute an anti-NOTCH therapeutic approach to reduce gamma-secretase activity.
细胞质域的 Notch 是一种膜结合的转录因子。配体结合最终导致跨膜结构域内的 γ-分泌酶切割，使细胞内结构域易位到细胞核并激活靶基因转录。组成性 Notch 信号与人类癌症如 T 细胞急性淋巴细胞白血病（T-ALL）有关。由于四跨膜蛋白已被牵涉到许多不同的信号过程中，我们评估了它们对 Notch 信号的潜在贡献。我们使用秀丽隐杆线虫中的遗传测定来鉴定 TSP-12 是几种细胞环境中 Notch 活性的正因子。然后，我们使用细胞培养系统表明，两种人类 TSP-12 同源物，TSPAN33 和 TSPAN5，促进 Notch 活性，并且可能在 γ-分泌酶切割步骤中起作用。我们还在秀丽隐杆线虫和人类细胞中获得了四跨膜蛋白功能冗余的证据。四跨膜蛋白的选择性抑制可能构成降低 γ-分泌酶活性的抗 NOTCH 治疗方法。
