Filamin A interacts with the coactivator MKL1 to promote the activity of the transcription factor SRF and cell migration

Kircher, Philipp; Hermanns, Constanze; Nossek, Maximilian; Drexler, Maria K.; Grosse, Robert; Fischer, Maximilian; Sarikas, Antonio; Penkava, Josef; Lewis, Thera C.; Prywes, Ron; Gudermann, Thomas; Muehlich, Susanne

doi:10.1126/scisignal.aad2959

Cited by 51 publications

(54 citation statements)

References 79 publications

(131 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Conversely, when expression of FLN is decreased, VSMCs return to the "contractile" phenotype, suggesting a key role in VSMCs phenotype switching [94]. In cultured cells, Flna has been shown to interact with Mkl1 and promote a Srfdependent smooth muscle transcriptional program [95].…”

Section: Discussionmentioning

confidence: 99%

Prune belly syndrome in surviving males can be caused by Hemizygous missense mutations in the X-linked Filamin A gene

et al. 2020

View full text Add to dashboard Cite

Background: Prune belly syndrome (PBS) is a rare, multi-system congenital myopathy primarily affecting males that is poorly described genetically. Phenotypically, its morbidity spans from mild to lethal, however, all isolated PBS cases manifest three cardinal pathological features: 1) wrinkled flaccid ventral abdominal wall with skeletal muscle deficiency, 2) urinary tract dilation with poorly contractile smooth muscle, and 3) intra-abdominal undescended testes. Despite evidence for a genetic basis, previously reported PBS autosomal candidate genes only account for one consanguineous family and single cases. Methods: We performed whole exome sequencing (WES) of two maternal adult half-brothers with syndromic PBS (PBS + Otopalatodigital spectrum disorder [OPDSD]) and two unrelated sporadic individuals with isolated PBS and further functionally validated the identified mutations. Results: We identified three unreported hemizygous missense point mutations in the X-chromosome gene Filamin ) in two related cases and two unrelated sporadic individuals. Two of the three PBS mutations map to the highly regulatory, stretch-sensing Ig19-21 region of FLNA and enhance binding to intracellular tails of the transmembrane receptor β-integrin 1 (ITGβ1). Conclusions: FLNA is a regulatory actin-crosslinking protein that functions in smooth muscle cells as a mechanosensing molecular scaffold, transmitting force signals from the actin-myosin motor units and cytoskeleton via binding partners to the extracellular matrix. This is the first evidence for an X-linked cause of PBS in multiple unrelated individuals and expands the phenotypic spectrum associated with FLNA in males surviving even into adulthood.

show abstract

Section: Discussionmentioning

confidence: 99%

Prune belly syndrome in surviving males can be caused by Hemizygous missense mutations in the X-linked Filamin A gene

et al. 2020

View full text Add to dashboard Cite

show abstract

“…Gene-expression profiles indicate that MKL1-regulated genes constitute a specific, small subset of megakaryocytic genes, encoding cytoskeletal remodeling factors and the ploidy regulator GEF-H1 (14,15,48). Two MKL1-regulated factors, FLNA and HIC-5, bind to MKL1, promote its activation, and thus induce feed-forward loops (49,50). Notably, our results show that human neonatal megakaryocytes have significant deficiencies of MKL1, FLNA, and HIC-5 and augment these factors in response to IGF2BP3 knockdown (see Figure 5E).…”

Section: Discussionmentioning

confidence: 99%

Neonatal expression of RNA-binding protein IGF2BP3 regulates the human fetal-adult megakaryocyte transition

Elagib¹,

Lu²,

Mosoyan³

et al. 2017

Journal of Clinical Investigation

View full text Add to dashboard Cite

“…MKL1/SRF signalling has key functions in tumour progression, such as mediating TGF-β-induced EMT and promoting cell migration and metastasis (Kircher et al, 2015; Medjkane et al, 2009; Morita et al, 2007). MKL1 is localized in the cytoplasm through binding to G-actin, but mitogenic or mechanical stimulation results in actin polymerization and translocation of MKL1 to the nucleus, where it serves a co-factor for SRF to activate expression of numerous proteins involved in cytoskeletal organization, contractility, and adhesion, including integrins, vinculin, and actin (Olson and Nordheim, 2010).…”

Section: Lamin A/c Interplay With Oncogenes and Tumour Suppressorsmentioning

confidence: 99%

Causes and consequences of nuclear envelope alterations in tumour progression

Bell

Lammerding

2016

European Journal of Cell Biology

112

View full text Add to dashboard Cite

Morphological changes in the size and shape of the nucleus are highly prevalent in cancer, but the underlying molecular mechanisms and the functional relevance remain poorly understood. Nuclear envelope proteins, which can modulate nuclear shape and organization, have emerged as key components in a variety of signalling pathways long implicated in tumourigenesis and metastasis. The expression of nuclear envelope proteins is altered in many cancers, and changes in levels of nuclear envelope proteins lamins A and C are associated with poor prognosis in multiple human cancers. In this review we highlight the role of the nuclear envelope in different processes important for tumour initiation and cancer progression, with a focus on lamins A and C. Lamin A/C controls many cellular processes with key roles in cancer, including cell invasion, stemness, genomic stability, signal transduction, transcriptional regulation, and resistance to mechanical stress. In addition, we discuss potential mechanisms mediating the changes in lamin levels observed in many cancers. A better understanding of cause-and-effect relationships between lamin expression and tumour progression could reveal important mechanisms for coordinated regulation of oncogenic processes, and indicate therapeutic vulnerabilities that could be exploited for improved patient outcome.

show abstract

Filamin A interacts with the coactivator MKL1 to promote the activity of the transcription factor SRF and cell migration

Abstract: F-actin mediates motility both at the leading edge of a cell and in the nucleus.

Cited by 51 publications

References 79 publications

Prune belly syndrome in surviving males can be caused by Hemizygous missense mutations in the X-linked Filamin A gene

Prune belly syndrome in surviving males can be caused by Hemizygous missense mutations in the X-linked Filamin A gene

Neonatal expression of RNA-binding protein IGF2BP3 regulates the human fetal-adult megakaryocyte transition

Causes and consequences of nuclear envelope alterations in tumour progression

Contact Info

Product

Resources

About