# Rho GTPase regulation in trophoblasts by c-Jun N-terminalkinase signaling

> **NIH NIH F31** · YALE UNIVERSITY · 2023 · $47,694

## Abstract

PROJECT SUMMARY
Placental development is critical in the early stages of pregnancy, as dysregulation of this process can lead to
intrauterine growth restriction of the fetus, preeclampsia, and miscarriage. A fundamental step in placental
development is the invasion of extravillous trophoblast cells into the endometrium of the uterus. A key mediator
of the invasive trophoblast phenotype is cytoskeletal remodeling driven by the activity of the small GTPase Rho.
Dynamic changes in the cytoskeleton are indispensable for initiating cell polarity and forming cell protrusions
and adhesions that drive cell migration, and the tightly coordinated regulation of these changes is critical for
successful placental development. However, the specific signaling mechanisms that regulate Rho GTPase
cytoskeletal remodeling during trophoblast invasion remain unclear. Previously published data have
suggested that the c-Jun-N-terminal kinase (JNK) subfamily of mitogen-activated protein kinases (MAPKs) may
be involved in trophoblast invasion, however the mechanism by which it accomplishes this is not well understood.
Recent screens from our lab have identified the Rho GTPase activating proteins (Rho GAPs) SYDE1 and SYDE2
as novel JNK substrates based on kinase-substrate docking interactions. Existing literature indicate roles of
SYDE1 and SYDE2 in migration in trophoblasts and cytoskeletal remodeling. It is therefore likely that SYDE1
and/or SYDE2 may be involved in a JNK signaling axis that regulates Rho GTPase cytoskeletal rearrangement
and migration during trophoblast invasion. The objective of this proposal is to elucidate how JNK modulates
SYDE1 and SYDE2 to control migration and invasion of trophoblasts. This proposal will determine the
functional consequences of JNK-mediated regulation of SYDE1 and SYDE2 in trophoblasts by examining the
effects on cell morphology, cytoskeletal organization, and migration in human trophoblast cells harboring SYDE1
or SYDE2 deletion or overexpression. Placental tissue samples will also be analyzed to examine clinical
relevance of JNK signaling through these proteins. GTPase biosensor assays will be used to determine whether
JNK phosphorylation of SYDE1 and SYDE2 positively regulates their activity as Rho GAPs. In vitro GTPase
assays will determine whether this mechanism is accomplished by affecting GAP enzymatic activity. In order to
establish whether any observed effects are dependent on JNK phosphorylation, JNK inhibitors and docking-site
mutant SYDE1 and SYDE2 will be used to ablate JNK-specific phosphorylation. Ultimately, identifying JNK and
small GTPase regulators as a key molecular players in trophoblast signaling, as well as understanding the
mechanisms by which they act, will allow them to be explored as molecular targets to treat severe pregnancy
complications related to aberrant trophoblast migration.

## Key facts

- **NIH application ID:** 10749994
- **Project number:** 1F31HD111285-01A1
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Claire Song
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $47,694
- **Award type:** 1
- **Project period:** 2023-09-01 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10749994

## Citation

> US National Institutes of Health, RePORTER application 10749994, Rho GTPase regulation in trophoblasts by c-Jun N-terminalkinase signaling (1F31HD111285-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10749994. Licensed CC0.

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