SPTAN1/Numb Axis Senses Cell Density To Restrain Cell Growth and Oncogenesis Through Hippo Signaling

Authors

Dongxue Su
Yuxi Li
Weiji Zhang
Huan Gao
Yao Cheng
Yongqiang Hou
Junhong Li
Yi Ye
Zhangjian Lai
Zhe Li
Haitao Huang
Jiaxin Li
Jinhuan Li
Mengyu Cheng
Cheng Nian
Na Wu
Zhien Zhou
Yunzhi Xing
Yu Zhao
He Liu
Jiayu Tang
Qinghua Chen
Lixin Hong
Wengang Li
Zhihai Peng
Bin Zhao
Randy L Johnson
Pingguo Liu
Wanjin Hong
Lanfen Chen
Dawang Zhou

Publication Date

10-16-2023

Journal

The Journal of Clinical Investigation

Abstract

The loss of contact inhibition is a key step during carcinogenesis. The Hippo-Yes-associated protein (Hippo/YAP) pathway is an important regulator of cell growth in a cell density-dependent manner. However, how Hippo signaling senses cell density in this context remains elusive. Here, we report that high cell density induced the phosphorylation of spectrin α chain, nonerythrocytic 1 (SPTAN1), a plasma membrane-stabilizing protein, to recruit NUMB endocytic adaptor protein isoforms 1 and 2 (NUMB1/2), which further sequestered microtubule affinity-regulating kinases (MARKs) in the plasma membrane and rendered them inaccessible for phosphorylation and inhibition of the Hippo kinases sterile 20-like kinases MST1 and MST2 (MST1/2). WW45 interaction with MST1/2 was thereby enhanced, resulting in the activation of Hippo signaling to block YAP activity for cell contact inhibition. Importantly, low cell density led to SPTAN1 dephosphorylation and NUMB cytoplasmic location, along with MST1/2 inhibition and, consequently, YAP activation. Moreover, double KO of NUMB and WW45 in the liver led to appreciable organ enlargement and rapid tumorigenesis. Interestingly, NUMB isoforms 3 and 4, which have a truncated phosphotyrosine-binding (PTB) domain and are thus unable to interact with phosphorylated SPTAN1 and activate MST1/2, were selectively upregulated in liver cancer, which correlated with YAP activation. We have thus revealed a SPTAN1/NUMB1/2 axis that acts as a cell density sensor to restrain cell growth and oncogenesis by coupling external cell-cell contact signals to intracellular Hippo signaling.

Keywords

Humans, Hippo Signaling Pathway, Protein Serine-Threonine Kinases, Spectrin, Adaptor Proteins, Signal Transducing, YAP-Signaling Proteins, Transcription Factors, Carcinogenesis, Cell Biology, Oncology, Cancer, Liver cancer, Signal transduction

Comments

Supplementary Materials

PMID: 37843276