(601k) 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.