Mechanobiology Institute Alumni
MBI Research Fellow 2009 – 2014
Dr. Cheng-han Yu received his B.Sc. in Physics (2000) from the National Taiwan University (NTU), gaining his early research experience in the Institute of Applied Mechanics, NTU with Prof. Chih-Kung Lee. He went on to complete his Ph.D. in biophysical chemistry (2002 – 2007) under the guidance of Prof. Jay T. Groves at the University of California, Berkeley.
His interest in the interactions between the cytoskeleton and cell adhesion motivated Cheng-han to join the research group of Prof. Michael P. Sheetz at the Mechanobiology Institute, Singapore (MBI) for his postdoctoral training (2009 – 2014). From 2010 to 2012, he was supported by the Young Postdoctoral Fellowship of National Science Council, Taiwan (NSC98-2917-I-564-165).
During his time at MBI, Cheng-han focused on the study of force-modulated molecular events that occur during cell-substrate adhesion. In particular he was interested in using nanopartitioned lipid bilayer membranes and super-resolution fluorescence microscopy to investigate integrin-mediated adhesion. .Read more about Dr Cheng-han Yu
An interest in integrin-mediated adhesions
In the human body, there are many surfaces on which a cell can grow. Each surface possesses unique properties, including its strength and rigidity. For example, bones more rigid than skin, while the skin in the elderly softer than that in babies. The ability of a cell to adhere to the underlying surface is mediated by adhesion structures, collectively known as cell-matrix adhesions.
Integrins are a primary component of cell matrix adhesions. These proteins exist as heterodimers that span the cell membrane and act as bidirectional signal transmitters to initiate various signalling pathways. These subsequently regulate cellular processes such as growth, migration, differentiation and apoptosis, or programmed cell death (Fig. 1).
The formation and function of cell-matrix adhesions are force-dependent, with responses varying between soft and rigid surfaces. As such, the outcome of signalling pathways regulated by integrin may differ depending on the rigidity of a surface. This is a contributing factor to various diseases, including cancer, where an uncontrolled expression of integrin is commonly observed. Understanding the influence of force, and mechanical signals, on integrin-mediated adhesion, would thus provide important information on clinically relevant cell processes such as wound healing, tissue regeneration and cancer therapy.
Driven by the importance of integrin-mediated adhesions, Cheng-han seized the opportunity to join the newly established MBI in 2009. With the advanced microscopy technology available at MBI, and through collaborations with the Institute of Materials Research and Engineering (IMRE), he continued his research until 2014, making significant contributions to the field in the process.
In one study (Yu et al. PNAS 2011), additional steps that occur in the early stages of cell adhesion on rigid substrates were described. These steps involve the binding of integrin to RGD (Arg-Gly-Asp) peptides. Here, initial clustering of activated integrins and recruitment of adhesion proteins (talin, paxillin and FAK) were found to occur independently of mechanical force. However, subsequent contraction of actomyosin and lamellipodial extension was force-dependent, as was the recruitment of vinculin. Furthermore, it was revealed that cells spread over a larger area on rigid surfaces compared to fluid membrane layers. These findings revealed that cell spreading mediated by integrin is indeed dependent on surface rigidity.
Exploring these early findings further, Cheng-han discovered that after prolonged adhesion, RGD-integrin clusters in fibroblasts form focal adhesions on rigid substrates. However, when forces cannot be stabilized, these adhesion complexes transform into podosomes (Yu et al. Cell Reports 2013). He found that the absence of forces at substrates stimulates a signalling pathway that recruits p85beta and locally enriches PIP3 at the adhesion sites, thus leading to the formation of podosomes.
Both focal adhesion and podosome formation are mediated by the activation of integrin, and their presence is closely related to cell motility. However, podosomes, are protrusive and are also associated with cell invasion. Cells such as macrophages would normally form podosomes when removing foreign substances via phagocytosis while aortic endothelial cells are known to form these structures during arterial vessel remodelling. In addition, podosomes are also formed in metastatic cancer cells as they migrate to other parts of body. Thus, understanding how forces mediate adhesion formation is important for understanding several clinically relevant cellular processes.
What the Future Holds
Cheng-han’s work was greatly supported by MBI’s ‘open laboratory concept’, which provided a constructive environment to build important partnerships and strengthen teamwork. Being amongst the initial research staff at MBI meant that these relationships grew with the institute, allowing collaborations to form, and expertise to be shared.
In 2014, Cheng-han leaves MBI to continue his academic career. This will be carried out at the Department of Anatomy in The University of Hong Kong, Hong Kong. Here, Cheng-han will focus on signal transduction at the molecular level and, in particular, will expand his work on integrin signalling and invadopodia dynamics in metastatic cancer cells.
Publications from Cheng-han’s time at MBI
H. Yu, J. B. K. Law, M. Suryana, H. Y. Low, M. P. Sheetz. Early integrin binding to Arg-Gly-Asp peptide activates actin polymerization and contractile movement that stimulates outward translocation. PNAS 108 (2011) 20585-20590. [PMID: 22139375]
H. Yu, N. B. Rafiq, A. Krishnasamy, K. L. Hartman, G. E. Jones, A. D. Bershadsky, M. P. Sheetz. Integrin-matrix clusters form podosome-like adhesions in the absence of traction forces. Cell Rep. 5 (2013) 1456-1468. [PMID: 24290759]
H. Yu, W. Luo, M. P. Sheetz. Spatial-temporal reorganization of activated integrins. Cell Adh. Migr. 6 (2012) 280-284. [PMID: 22863737]
Iversen, H. L. Tu, W. C. Lin, S. M. Christensen, S. M. Abel, J. Iwig, H. J. Wu, J. Gureasko, C. Rhodes, R. S. Petit, S. D. Hansen, P. Thill, C. H. Yu, D. Stamou, A. K. Chakraborty, J. Kuriyan, J. T. Groves. Ras activation by SOS: Allosteric regulation by altered fluctuation dynamics. Science 345 (2014) 50-54. [PMID: 24994643]
Yamauchi, Y. Y. Hou, A. K. Guo, H. Hirata, W. Nakajima, A. K. Yip, C. H. Yu, I. Harada, K. H. Chiam, Y. Sawada, N. Tanaka, K. Kawauchi. p53-mediated activation of the mitochondrial protease HtrA2/Omi prevents cell invasion. J. Cell Biol. 204 (2014) 1191-1207. [PMID: 24662565]
Iskratsch, C. H. Yu, A. Mathur, S. M. Liu, V. Stevenin, J. Dwyer, J. Hone, E. Ehler, M. Sheetz. FHOD1 Is Needed for Directed Forces and Adhesion Maturation during Cell Spreading and Migration. Dev. Cell 27 (2013) 545-559. [PMID: 24331927]
W. Luo, C. H. Yu, Z. Z. Lieu, J. Allard, A. Mogilner, M. P. Sheetz, A. D. Bershadsky. Analysis of the local organization and dynamics of cellular actin networks. J. Cell Biol. 202 (2013) 1057-1073. [PMID: 24081490]
D. Lynch, N. C. Gauthier, N. Biais, A. M. Lazar, P. Roca-Cusachs, C. H. Yu, M. P. Sheetz. Filamin depletion blocks endoplasmic spreading and destabilizes force-bearing adhesions. Mol. Biol. Cell 22 (2011) 1263-1273. [PMID: 21325628]