# Mechanism and Regulation of STRIPAK–SLMAP in Hippo Signaling

> **NIH NIH R01** · UT SOUTHWESTERN MEDICAL CENTER · 2021 · $391,773

## Abstract

Project Summary
Dynamic protein phosphorylation regulates virtually all biological processes. Selective dephosphorylation of
specific substrates or specific sites on a given substrate is critical for key cellular events. Our recent studies have
uncovered an unusual example of site-specific dephosphorylation by the multi-subunit Striatin-interacting
phosphatase and kinase complex called STRIPAK, which controls Hippo pathway activation. The Hippo pathway
is critical for tissue homeostasis and tumor suppression in multicellular organisms. Dysregulation of this pathway
drives tumor formation in flies, mice, and humans. Through cell-surface receptors and cytoskeletal complexes
(e.g. NF2), extracellular signals, including cell-cell contact, activate a core kinase cascade formed by the Hippo
kinases MST1/2, the NDR family kinases LATS1/2, and the adaptor proteins SAV1 and MOB1. Activated
LATS1/2 phosphorylate and prevent the nuclear accumulation of the transcription factors YAP/TAZ. When the
Hippo pathway is off, YAP/TAZ translocate to the nucleus and form functional hybrid transcriptional factors with
TEADs to promote the transcription of proliferative and pro-survival genes. Activation of MST1/2 initiates Hippo
signaling and requires trans-autophosphorylation in the T-loop (MST2 T180). We have recently shown that the
PP2A complex STRIPAK blocks MST2 activation through feedback inhibition. Active MST2 auto-phosphorylates
multiple sites in the linker. The adaptor protein SLMAP in STRIPAK binds the phospho-linker and promotes
MST2 pT180 dephosphorylation, thus ensuring low steady-state MST2 activation. SAV1 promotes MST2
activation by suppressing STRIPAKSLMAP-mediated dephosphorylation of MST2 pT180. The physiological
function, regulation, and mechanism of action of STRIPAKSLMAP remain unresolved. We hypothesize that
STRIPAKSLMAP integrates upstream inputs through SAV1 to control MST1/2 activation. Because
STRIPAKSLMAP contains both a kinase and a phosphatase, the delicate balance between the opposite catalytic
activities of the two enzymes in the same complex may play a critical role in toggling the activation status of
Hippo signaling. Thus, understanding the architecture, assembly mechanism, and regulation of STRIPAKSLMAP
is crucial to the eventual understanding of how the core Hippo pathway is regulated by upstream signals. This
proposal aims to determine the molecular mechanism and structural basis of this opposing regulation of the
Hippo kinases MST1/2 by SAV1 and STRIPAKSLMAP, and to dissect the architecture, assembly mechanism, and
regulation of STRIPAKSLMAP in the context of Hippo signaling. This research will significantly advance our
fundamental understanding of the regulation of the Hippo signaling network and may uncover novel ways of
exploiting defects in the Hippo pathway to treat human diseases.

## Key facts

- **NIH application ID:** 10242873
- **Project number:** 5R01GM132275-03
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** Xuelian Luo
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $391,773
- **Award type:** 5
- **Project period:** 2019-09-23 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10242873

## Citation

> US National Institutes of Health, RePORTER application 10242873, Mechanism and Regulation of STRIPAK–SLMAP in Hippo Signaling (5R01GM132275-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10242873. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*