Repeated Interactions Between ErbB1 Receptors and the Impact On Signal Initiation

Repeated Interactions between ErbB1 Receptors and the Impact on Signal Initiation

Meghan M. McCabe¹, Shalini T. Low-Nam², Adam Halasz³, Diane S. Lidke^4,5, Bridget S. Wilson^4,5, and Jeremy S. Edwards^1,5,6

¹Department of Chemical and Nuclear Engineering, University of New Mexico, Albuquerque, New Mexico, USA.

²Department of Chemistry and Biochemistry, South Dakota State University, Brookings, South Dakota, USA

³Department of Mathematics, West Virginia University, Morgantown, West Virginia, USA.

⁴Department of Pathology, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, USA.

⁵Cancer Research and Treatment Center, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, USA.

⁶Molecular Genetics and Microbiology, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, USA.

The ErbB family of receptors is a group of four tyrosine kinases (ErbB1/2/3/4) that are activated via ligand binding and subsequent formation of homo and heterodimers.  The main function of the ErbB family is to mediate important cellular processes such as homeostasis, pathology, and development as well as the interactions between cells .  Specifically, ErbB receptors play an important part in the regulation of cell growth, proliferation, differentiation, and apoptosis.  Given these important roles in normal cell development, it is not surprising that in the early 1980's the ErbB receptor family was implicated in the progression of cancers such as breast, lung, and bladder. More specifically, the overexpression of ErbB1 is known to cause uncontrolled cell proliferation.  Due to this strong link between ErbB1 and cancer, it is important to understand signal initiation and transduction mechanisms associated with this receptor.  Traditionally, experimental methods are used to understand ErbB1 signaling.  Single particle tracking (SPT) experiments are used to visualize ErbB1 behavior within the live cell context.  The experimental team at University of New Mexico reported seeing repeated interactions between ErbB1 receptors during SPT experiments.  We believe the repeated interactions are critical to receptor phosphorylation and signal initiation in ErbB1.  An important caveat of these SPT experiments is that receptors must be labeled at a sufficiently low density to permit discrimination between individual proteins.   Although SPT experiments have yielded useful kinetic and diffusion parameters, the contributions of the unlabeled (and therefore unseen) species remain unexplored.  A model must be built in order to resolve these unlabeled species. The key to this model is ability to see when the labeled receptors interact with unlabeled receptors as well as other labeled receptors allowing us to investigate repeated interactions. While there are many models to simulate ErbB1 receptor behaviors, most lack a fundamental connection to experimental data.  In a step towards making the connection between experiments and modeling stronger, the overall goal of this work is to develop a model using parameters from live cell imaging to investigate the impact of repeated interactions seen in SPT on ErbB1 phosphorylation and signal initiation.