Besides biochemical and molecular regulation, the migration and invasion of cells
is controlled by the environmental mechanics and cellular mechanics. Hence, the
mechanical phenotype of cells, such as fibroblasts, seems to be crucial for the
migratory capacity in confined 3D extracellular matrices. Recently, we have shown
that the migratory and invasive capacity of mouse embryonic fibroblasts depends on
the expression of the Rho-GTPase Rac1, similarly it has been demonstrated that the
Rho-GTPase Cdc42 affects cell motility. The p21-activated kinase (PAK) is an effector
down-stream target of both Rho-GTPases Rac1 and Cdc42, and it can activate via the
LIM kinase-1 its down-stream target cofilin and subsequently support the cell migration
and invasion through the polymerization of actin filaments. Since Rac1 deficient cells
become mechanically softer than controls, we investigated the effect of group I PAKs
and PAK1 inhibition on cell mechanics in the presence and absence of Rac1. Therefore,
we determined whether mouse embryonic fibroblasts, in which Rac1 was knockedout,
and control cells, displayed cell mechanical alterations after treatment with group I
PAKs or PAK1 inhibitors using a magnetic tweezer (adhesive cell state) and an optical
cell stretcher (non-adhesive cell state). In fact, we found that group I PAKs and Pak1
inhibition decreased the stiffness and the Young’s modulus of fibroblasts in the presence
of Rac1 independent of their adhesive state. However, in the absence of Rac1 the
effect was abolished in the adhesive cell state for both inhibitors and in their nonadhesive
state, the effect was abolished for the FRAX597 inhibitor, but not for the IPA3
inhibitor. The migration and invasion were additionally reduced by both PAK inhibitors
in the presence of Rac1. In the absence of Rac1, only FRAX597 inhibitor reduced their
invasiveness, whereas IPA3 had no effect. These findings indicate that group I PAKs
and PAK1 inhibition is solely possible in the presence of Rac1 highlighting Rac1/PAK I
(PAK1, 2, and 3) as major players in cell mechanics.
| Identifer | oai:union.ndltd.org:DRESDEN/oai:qucosa:de:qucosa:84502 |
| Date | 03 April 2023 |
| Creators | Mierke, Claudia Tanja, Puder, Stefanie, Aermes, Christian, Fischer, Tony, Kunschmann, Tom |
| Publisher | Frontiers Research Foundation |
| Source Sets | Hochschulschriftenserver (HSSS) der SLUB Dresden |
| Language | English |
| Detected Language | English |
| Type | info:eu-repo/semantics/publishedVersion, doc-type:article, info:eu-repo/semantics/article, doc-type:Text |
| Rights | info:eu-repo/semantics/openAccess |
| Relation | 2296-634X, 13 |
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