# Salt-inducible kinases transduce mechanical forces into the specification of the pancreatic endocrine lineage

## TL;DR

This study shows how mechanical forces influence the development of pancreatic endocrine cells through salt-inducible kinases (SIKs).

## Contribution

The paper identifies SIKs as key mediators linking F-actin dynamics to YAP1 activity during endocrinogenesis.

## Key findings

- SIKs mediate F-actin-triggered changes in YAP1 activity during endocrinogenesis.
- Increased SIK expression promotes differentiation into endocrine progenitors.
- SIK inhibition reduces endocrine progenitor differentiation.

## Abstract

The extracellular matrix-F-actin-Yes-associated protein 1 (YAP1)-Notch mechanosignaling axis is a gatekeeper in the fate decisions of bipotent pancreatic progenitors (bi-PPs). However, the link between F-actin dynamics and YAP1 activity remains poorly understood. Here, we identify salt-inducible kinases (SIKs) as mediators of F-actin-triggered changes in YAP1 activity. Interestingly, sodium chloride treatment promotes the differentiation of bi-PPs into NEUROG3+ endocrine progenitors (EPs) through enhanced SIK expression. Consistently, the pan-SIK inhibitor HG-9-09-01 (HG) inhibits latrunculin B (LatB)-induced EP differentiation via nuclear YAP1 accumulation. Unexpectedly, withdrawal of HG after a 12-h treatment increased SIK expression by a negative feedback mechanism, leading to significantly enhanced endocrinogenesis. Therefore, the combined treatment of bi-PPs with LatB and HG for 12 h boosted endocrinogenesis, ultimately leading to an increased number of beta cells. In summary, we identify SIKs as new transducers of mechanotransduction-triggered induction of pancreatic endocrine cell fates.

•SIKs act as the link between F-actin and YAP1 during endocrinogenesis•Increased expression of SIKs promotes endocrine progenitor differentiation•SIK inhibition reduces endocrine progenitor differentiation

SIKs act as the link between F-actin and YAP1 during endocrinogenesis

Increased expression of SIKs promotes endocrine progenitor differentiation

SIK inhibition reduces endocrine progenitor differentiation

Semb and colleagues identify SIKs as new transducers of mechanotransduction-triggered induction of pancreatic endocrine cell fates. Pharmacologically increasing SIK expression/activity enhances endocrinogenesis and beta cell differentiation.