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Grosse group


Our research is funded by:
 
CIBSS      DFG      HFSP      SANST
 

I. Cytoskeletal Regulation of Invasive Cell Migration


Our group has a long-standing interest in invasive cancer cell migration. In particular, we study the role of the actin cytoskeleton and how deregulation of actin dynamics impacts on invasive migration. It would be of importance to identify novel concepts for pharmacological targeting to interfere with actin-regulating factors such as actin nucleation and assembly proteins. Many of these actin assembly factors are under the control of Rho-GTPase signaling but also serine-threonine kinase regulations, including the formin family of proteins. We have been studying formins and their role in cancer cell invasion, both, from a cytoskeletal as well as gene regulatory aspect. In the latter case, the actin-controlled SRF transcriptional cofactor MRTF is a key factor in translating cellular actin dynamics into gene expression essential for cell adhesion and migration.

Key Papers:
1. Nürnberg, A., Kitzing, T., Grosse, R. (2011). Nucleating actin for invasion. Nature Reviews Cancer, 11(3), 117–187.
2. Purvanov, V., Holst, M., Khan, J., Baarlink, C., Grosse, R. (2014). G-protein-coupled receptor signaling and polarized actin dynamics drive cell-in-cell invasion. ELife, 2014(3).
3. Hinojosa, L. S., Holst, M., Baarlink, C., Grosse, R. (2017). MRTF transcription and Ezrin-dependent plasma membrane blebbing are required for entotic invasion. Journal of Cell Biology, 216(10), 3087–3095.
4. Wang, Y., Arjonen, A., Pouwels, J., Ta, H., Pausch, P., Bange, G., Engel, U., Pan, X., Fackler, O. T., Ivaska, J., Grosse, R. (2015). Formin-like 2 Promotes β1-Integrin Trafficking and Invasive Motility Downstream of PKCα. Developmental Cell, 34(4), 475–483.
5. Kitzing, T. M., Sahadevan, A. S., Brandt, D. T., Knieling, H., Hannemann, S., Fackler, O. T., Großhans, J., Grosse, R. (2007). Positive feedback between Dia1, LARG, and RhoA regulates cell morphology and invasion. Genes and Development, 21(12), 1478–1483.
6. Brandt, D. T., Baarlink, C., Kitzing, T. M., Kremmer, E., Ivaska, J., Nollau, P., Grosse, R. (2009). SCAI acts as a suppressor of cancer cell invasion through the transcriptional control of β1-integrin. Nature Cell Biology, 11(5), 557–568.
7. Kitzing, T. M., Wang, Y., Pertz, O., Copeland, J. W., Grosse, R. (2010). Formin-like 2 drives amoeboid invasive cell motility downstream of RhoC. Oncogene, 29(16), 2441–2448.

Entosis
Entotic cell-in-cell invasion | MCF10A cells expressing LifeAct-mCherry (red) or -GFP (green) were monitored over time to follow entotic cell-in-cell invasion (from Purvanov et al., eLife, 2014).


Live cell invasion into a collagen matrix | Human fibrosarcoma cells invading into a FITC-labelled collagen matrix (gray). Scale bar, 15 µm; time stamp, h:min:s.

Actin
Formin Domain Organization and Regulation | Formins are multidomain proteins. The FH2 (formin homology 2) domain is highly conserved within the formin family and polymerizes F-actin. The FH1 domain is required for (monomeric) G-actin recruitment. The formin is rendered inactive through an intramolecular interaction between the DAD (diaphanous autoinhibitory domain) and the DID (diaphanous inhibitory domain). Active Rho GTPases such as Rho, Rac1, CDC42, or Rif trigger formin activity through release of autoinhibition. Further signals such as lipidation, farnesylation, or phosphorylation have been shown to regulate activation and localization (from Grikscheit and Grosse, Trends in Biochemical Sciences, 2016).

 

II. Regulation and Functions of Actin and Chromatin Dynamics in Cell Division


Part of our research aims at understanding the functions of nuclear F-actin in somatic cells during mitosis. We recently identified a nuclear actin cytoskeleton that forms during daughter cell expansion after mitotic exit. These actin filaments appear to facilitate nuclear volume expansion and chromatin decondensation, an essential process for proper genome organization after cell division. Work in our laboratory aims at further elucidating the molecular players and mechanisms on the one hand and the functional consequences for nuclear organization and cellular behavior such as differentiation or proliferation on the other.

Key Papers:
1. Baarlink, C., Plessner, M., Sherrard, A., Morita, K., Misu, S., Virant, D., Kleinschnitz, E.-M., Harniman, R., Alibhai, D., Baumeister, S., Miyamoto, K., Endesfelder, U., Kaidi, A., Grosse, R. (2017). A transient pool of nuclear F-actin at mitotic exit controls chromatin organization. Nature Cell Biology, 19(12), 1389–1399.
2. Plessner, M., Grosse, R. (2019). Dynamizing nuclear actin filaments. Current Opinion in Cell Biology, 56, 1–6.


Actin and Chromatin during Cell Division | Fibroblasts labelled for endogenous actin (green) and chromatin (red) undergoing mitosis (from Baarlink et al., NCB, 2017).

 

III. Extracellular Cues for Nuclear Actin Polymerization


We have previously identified signal-regulated nuclear actin assembly through growth serum stimulation or via integrin-mediated signaling involving the LINC complex. Currently, we are trying to elucidate the signaling events that promote rapid and transient nuclear actin polymerization through cell surface receptors. Efforts in the laboratory try to decipher the physiological ligands and their receptors as well as the functional consequences of nuclear actin network formation for chromatin organization. In addition, we are studying the role of nuclear actin assembly during and for invasive cell migration.

Key Papers:
1. Tsopoulidis, N., Kaw, S., Laketa, V., Kutscheidt, S., Baarlink, C., Stolp, B., Grosse, R. Fackler, O. T. (2019). T cell receptor–triggered nuclear actin network formation drives CD4+ T cell effector functions. Science Immunology, 4(31), eaav1987.
2. Baarlink, C., Wang, H., Grosse, R. (2013). Nuclear actin network assembly by formins regulates the SRF coactivator MAL. Science, 340(6134), 864–867.
3. Baarlink, C., Plessner, M., Sherrard, A., Morita, K., Misu, S., Virant, D., Kleinschnitz, E.-M., Harniman, R., Alibhai, D., Baumeister, S., Miyamoto, K., Endesfelder, U., Kaidi, A., Grosse, R. (2017). A transient pool of nuclear F-actin at mitotic exit controls chromatin organization. Nature Cell Biology, 19(12), 1389–1399.
4. Plessner, M., Grosse, R. (2015). Extracellular signaling cues for nuclear actin polymerization. European Journal of Cell Biology, 94(7–9), 359–362.

Cues
Fibronectin- and Serum/LPA-mediated nuclear actin polymerization.

 

IV. Optogenetic Control of the Actin Cytoskeleton


We are continuing our efforts in developing and applying novel tools to control cytoskeletal effects and functions using optogenetics and live cell imaging. Such light-regulatable tools shall be useful to spatiotemporally manipulate and study specific actin-dependent effects for cell behavior such as cell division and migration. These studies will provide a better understanding on the functions of actin-regulating factors in living cells.

Key Papers:
1. Baarlink, C., Wang, H., Grosse, R. (2013). Nuclear actin network assembly by formins regulates the SRF coactivator MAL. Science, 340(6134), 864–867.
2. Baarlink, C., Plessner, M., Sherrard, A., Morita, K., Misu, S., Virant, D., Kleinschnitz, EM, Harniman, R., Alibhai, D., Baumeister, S., Miyamoto, K., Endesfelder, U., Kaidi, A., Grosse, R. (2017). A transient pool of nuclear F-actin at mitotic exit controls chromatin organization. Nature Cell Biology, 19(12), 1389–1399.
3. Grobe, H., Wüstenhagen, A., Baarlink, C., Grosse, R., Grikscheit, K. (2018). A Rac1-FMNL2 signaling module affects cellcell contact formation independent of Cdc42 and membrane protrusions. PLoS ONE, 13(3), 1–17.
4. Grikscheit, K., Frank, T., Wang, Y., Grosse, R. (2015). Junctional actin assembly is mediated by Formin-like 2 downstream of Rac1. Journal of Cell Biology, 209(3), 367–376.

Opto-Cofilin


Light-regulated nuclear export of Cofilin | Left: Cofilin-1 fused to LOV2-Jα containing a light-regulatable nuclear export sequence (LEXY). Right: Fibroblasts labelled for endogenous nuclear actin expressing Opto-Cofilin. The green bar indicates 488 nm illumination to activate Opto-Cofilin and actively induce nuclear export (from Baarlink et al., NCB, 2017; for LEXY module, please see Niopek et al., Nat. Comm., 2016).

 

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