Her2 Dimerization, a refresher of oncogenic signaling

['lizbeth]

http://www.biooncology.com/research-education/hdis/her2-dimerization/

HER2 dimerization: a key component of oncogenic signaling in HER2+ breast cancer

The HER family

The HER family is composed of 4 receptor tyrosine kinases that must pair, or dimerize, to activate downstream signaling¹:


EGFR (HER1)
HER2
HER3
HER4

The role of dimerization in HER2+ disease

Preclinical studies indicate that HER dimerization, or receptor pairing, is a critical step in HER activation.¹ While the receptors of the HER family are important mediators of normal cell growth and development, HER activation has also been implicated in cancer development and progression.¹⁰
In normal cell growth, dimerization is an essential requirement of HER functionality and signaling, and it occurs between 2 of the same receptors (homodimerization) or 2 different receptors (heterodimerization).¹
However, in HER2+ disease, HER2 overexpression is associated with excessive dimerization that contributes to cell survival, cell proliferation, and tumorigenesis.⁶
http://www.biooncology.com/research-education/hdis/images/HERfamily.png <cite>The HER family of receptors.</cite>
(http://www.biooncology.com/research-education/hdis/images/HERfamily_lg.png) Ligand binding and HER activation

Each HER family receptor has 3 domains: the extracellular, transmembrane, and intracellular domains, all of which are necessary for receptor activation and intracellular signaling. In order to activate downstream signaling, receptors must dimerize utilizing the dimerization sub-domain (known as sub-domain II) located on the extracellular domain of the receptor.¹⁰
EGFR (HER1), HER3, and HER4 naturally exist in a “closed” conformation. In the closed position, the dimerization sub-domain (sub-domain II) is hidden or inaccessible, and as a result, the receptor is unable to form dimers. Ligand binding to these receptors leads to a conformational change, exposing sub-domain II and enabling the receptor to dimerize and initiate downstream signaling. HER2 is the only receptor in the HER family that exists in a continuously open conformation ready to dimerize without the need for ligand binding.^3,11
HER2 dimerization: critical for tumor growth

When HER family members dimerize, the intracellular domains of the paired receptors are phosphorylated, resulting in the activation of cell proliferation and cell survival pathways.¹²
In HER2+ disease, the overexpression of HER2 is associated with overactive HER2 dimerization, abnormal signaling, and ultimately tumor growth.⁶
Dimerization: an important driver of oncogenic signaling

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['lizbeth]

Receptor-ology 101 by Candance Pert, Ph.D. Everything You Need to Feel Go(o)d

"To begin with, virtually every cell in the body is studded with thousands of tiny structures called receptors. Like the sense organs - the eyes, nose, and ears - the job of the receptors is to pick up signals coming at them from the surrounding space. The They're so important that a full 40 percent of our DNA is devoted to making sure that they're perfectly reproduced from generation to generation.

Once the receptors received a signal, the information is transferred to deep within the cell's interior, where tiny engines roar into action and initiate key processes. Data coming in this way directs cell division and growth, cell migration for attacking enemies and making repairs, and cell metabolism to conserve or spend energy - to name just a few of the receptor-activated activities.

The signal comes from other cells and is carried by a juice that we call information substance. These juices from the brain, sexual organs, gut, and heart - literally everywhere - communicate cell to cell, providing an infrastructure for the 'conversation' going on through the bodymind. You know these juices as hormones, neurotransmitters, and peptides; and we scientists refer to all three with one word: ligand. This term is from ligare, a Latin word meaning "to bind", and is used because of the way that the substances latch on so tightly to the cell's surface receptors.

Information-carrying ligands are responsible for 98 percent of all data transfer in body and brain. The remaining 2 percent of communication takes place at the synapse, between brain cells firing and releasing neurotransmitters across a gap to hit receptors on the other side.

. . . There are only 200 peptides mapped in the brain and body, each one sounding a complex emotional chord - such as bliss, hunger, anger, relaxation, or satiety - when their signal is received by the cell. I've devoted my 30-plus career to studying peptides such as endorphins and other substances.

['lizbeth]

"In addition, everyone should know that most ligands have chemical equivalents found outside the body, such as Valium, marijuana, cocaine, alcohol, and caffeine, to name a few.

"You've now leaned about the two components that make up this bodymind communication system - the receptor and the ligand. These are what I have called the 'molecules of emotion'. But how do the two find each other across the vast reaches of intercellular space, hook up - or bind - and them transfer vital information to affect cellular, bodywide activity?

We used to explain the attraction by a quality called receptor specificity, which is that each receptor is specifically shaped to fit one and only one ligand. A lock-and-key model helped with visualizing this method of connecting, or binding. The 'key' (a peptide) floats by until it finds its perfect 'keyhole' (the receptor). The key inserts into the keyhole opening the 'lock' of the cell, and cellular activities begin.

While this is partially accurate, we now understand a more dynamic relation ship between ligand and receptor, involving something called 'vibratory attraction.' Sitting on the surface of the cell, the receptor wiggles and shimmies, changing from one configuration to another in a constant state of flux. This dance creates a vibration that resonates with a ligand vibrating at the same frequency, and they begin to resonate together.

Cellular resonance - its like when you pluck one string on two different guitars in the same room - one will resonate with the other, both striking the same note. This creates a force of attraction the way that peptides resonated with their receptors and come together to strike that emotional chord as they bind. And that's when the music begins!

I've said the emotions are the link between the physical body and nonphysical states of consciousness, and the receptors on every cell are where this happens! The attracting vibration is the emotion, and the actual connection - peptide to receptor - is the manifestation of the feeling in the physical world. That's why I call peptides and their receptors the molecules of emotions."

Candace Pert, Ph.D, New-Paradigm Physiology, Everything you need to know to feel Go(o)d