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Single-molecule functional anatomy of endogenous HER2-HER3 heterodimers.

ABSTRACT: Human epidermal growth factor receptors (HERs) are the primary targets of many directed cancer therapies. However, the reason a specific dimer of HERs generates a stronger proliferative signal than other permutations remains unclear. Here, we used single-molecule immunoprecipitation to develop a biochemical assay for endogenously-formed, entire HER2-HER3 heterodimers. We observed unexpected, large conformational fluctuations in juxta-membrane and kinase domains of the HER2-HER3 heterodimer. Nevertheless, the individual HER2-HER3 heterodimers catalyze tyrosine phosphorylation at an unusually high rate, while simultaneously interacting with multiple copies of downstream signaling effectors. Our results suggest that the high catalytic rate and multi-tasking capability make a concerted contribution to the strong signaling potency of the HER2-HER3 heterodimers.

SUBMITTER: Choi B

PROVIDER: S-EPMC7176432 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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Single-molecule functional anatomy of endogenous HER2-HER3 heterodimers.

Choi Byoungsan B Cha Minkwon M Eun Gee Sung GS Lee Dae Hee DH Lee Seul S Ehsan Muhammad M Chae Pil Seok PS Heo Won Do WD Park YongKeun Y Yoon Tae-Young TY

eLife 20200408

Human epidermal growth factor receptors (HERs) are the primary targets of many directed cancer therapies. However, the reason a specific dimer of HERs generates a stronger proliferative signal than other permutations remains unclear. Here, we used single-molecule immunoprecipitation to develop a biochemical assay for endogenously-formed, entire HER2-HER3 heterodimers. We observed unexpected, large conformational fluctuations in juxta-membrane and kinase domains of the HER2-HER3 heterodimer. Neve ...[more]

PMID: 32267234

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